Advances in Heterocyclic Chemistry, Volume 38

Advances in

Heterocyclic Chemistry Volume 38

Editorial Advisory Board R . A. Abramovitch, Clemson, South Carolina A. Albert, Canberra, Australia A. T. Balaban, Bucharest, Romania

A. J. Boulton, Norwich, England

H. Dorn, Berlin, G.D.R. S. Gronowitz, Lund, Sweden

T. Kametani, Tokyo, Japan C. W . Rees FRS, London, England

Yu. N. Sheinker, Moscow, U.S.S.R.

E. C . Taylor, Princeton, New Jersey M. TiSler, Ljubljana, Yugoslavia J . A . Zoltewicz, Gainesville, Florida

Advances in

HETEROCYCLIC CHEMISTRY

Edited by ALAN R. KATRITZKY FRS Kenan Professor of Chemistry Department of Chemistry Universify of Florida Gainesville, Florida

Volume 38 ACADEMIC PRESS,INC. (Horcourt Brace Jovanovich, Publishers)

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gn7fi.54321

Contents CONTRIBUTORS ..............................................................

vii

PREFACE ....................................................................

ix

Recent Advances in the Chemistry of Dihydroazines ALEXANDER L. WEIS 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . II. Scope and Limitations . . . . 111. General Overview o IV. Dihydropyridazines ................. V. Dihydropyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . VI. Dihydro-l,2,3-triazines . . . . . . VII. Dihydro-I ,2,4-triazines VIII. Dihydro-l,3,5-triazines IX. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 6 6 23 45 82 83 91 102

Recent Advances in the Chemistry of Benzisothiazoles and Other Polycyclic Isothiazoles MICHAEL DAVIS

....... .. .. ... ..............................................

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. 1,2-Benzisothiazoles 111. I ,2-Benzisothiazolin-

IV. 2,l-Benzisothiazoles . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . , . . . . . V. Other lsothiazole Systems . . VI. Selenium and Tellurium Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

106 107 116 122 130 132

1,4-Benzothiazines, Dihydro- 1,4-benzothiazines, and Related Compounds C . BROWNAND R. M. DAVIDSON

..

I. Introduction

11. Natural Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Pharmacology of 1,4-Benzothiazines and Their Derivatives . . . . . . . . . . . . . . . . . . . . .

IV. V. VI. VII.

Agricultural Uses . . . . . . . . . Industrial Uses . . . . . . . . . . . Synthesis . . . . . . . . . . . . . . . . Reactions of 1,4-Benzothiazines

. . . . . . . . . . . . . . .. . . ...... ....... ..... . . . . . . . . . . . . . . .. ... . . . .. . . . . . , . . .. . . . . . . . . .

............. .....

V

135 138 142 145 146 146 167

vi

CONTENTS

The Chemistry of Hydantoins c. AVENDANO L6PEZ AND G.GONZhLEZ TRIGO I. 11. 111. IV. V.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods of Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physicochemical Studies on Hydantoins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reactivity of Hydantoins and Their Derivatives ............................... Uses and Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Recent Progress in Barbituric Acid Chemistry JACEK T. BOJARSKI, JERZY L. MOKROSZ, HENRYKJ . AND MARIAH. PALUCHOWSKA

178 178 203 209 224

BART6N,

I. Introduction ................................................. 11. Physicochemical Properties of Barbiturates 111. Reactivity of Barbiturates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

IV. Analytical Methods for Barbiturates . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . 231 . . . . . . . . . . 263 . . . . . . . . . . 288

VI. Closing Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Addendum .................................

291

Heterocyclic P-Enamino Esters, Versatile Synthons in Heterocyclic Synthesis HEINRICH WAMHOFF

............................ 300 .......................................... 111. Structure and Spectral Properties . . . . . . . . . . . . . . . . . . . . . 309 I. Introduction . . . . . . . .

11. Synthetic Approaches

IV. General Consideration V. Electrophilic Attacks on the 2-Amino Group (or the Carbon-3 Atom). Synthesis of Polynuclear Heterocyclic Systems . . . . . . . . . . . . . . . V1. Nucleophilic Attacks of Amines and Diamines .............. VII. Cycloadditions and Reactions with Acetylenic Esters .......................... VIII. 2-(Triphenylphosphorylidenamino)Esters. The Cycloaddition-Ring Enlargement Sequence ................................... IX. Photochemistry .................................... X. Heterocyclic P-Enamino Nitriles ........................ XI. Conclusion and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

INDEX OF TITLES CUMULATIVE

....................................

343 347 351 351

369

Contributors Numbers in parentheses indicate the pages on which the authors' contributions begin.

HENRYKJ. BARTON,Department of Organic Chemistry, Nicolaus Copernicus Academy of Medicine, 30-048 Krakdw, Poland (229) JACEK T . BOJARSKI,Department of Organic Chemistry, Nicolaus Copernicus Academy of Medicine, 30-048 Krakdw, Poland (229) C . BROWN,The Chemical Laboratory, University of Kent at Canterbury, Canterbury, Kent CT2 7NH, England (1 35) R. M . DAVIDSON, The Chemical Laboratory, University of Kent at Canterbury, Canterbury, Kent CT2 7NH, England (1 35) MICHAELDAVIS,Department of Organic Chemistry, La Trobe Universiry, Bundoora, Victoria 3083, Australia (105) C. AVENDA~~O LOPEZ,Departamento de Quimica Orgdnica y Farmace'utica, Facultad de Farmacia, Universidad Complutense, Madrid-3, Spain ( 177) JERZY L. MOKROSZ,Department of Organic Chemistry, Nicolaus Copernicus Academy of Medicine, 30-048 Krakdw, Poland (229) MARIAH. PALUCHOWSKA, Department of Organic Chemistry, Nicolaus Copernicus Academy of Medicine, 30-048 Krakdw, Poland (229) G. GONZALEZTRIGO,Departamento de Quimica Orgdnica y Farmace'utica, Facultad de Farmacia, Universidad Complutense, Madrid-3, Spain ( 177) HEINRICHWAMHOFF,Institut fur Organische Chemie und Biochemie der Universitat Bonn, 0-5300 Bonn 1 , Federal Republic of Germany (299) ALEXANDERL. WEIS, Department of Organic Chemistry, The Weizmann Institute of Science, 76 100 Rehovot, Israel (1)

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Preface Volume 38 of Advances in Heterocyclic Chemistry is composed of six chapters which deal with six diverse classes of heterocyclic compounds. A. L. Weis of the Weizmann Institute gives the first authoritative account of the chemistry of dihydroazines, a group of compounds that until recently has been rather neglected. Two chapters deal with sulfur-containing compounds. The benzisothiazoles and other polycyclic isothiazoles are covered by M. Davis, in a sequel to earlier reviews in Advances in Heterocyclic Chemistry, Volumes 14 and 15. IP-Benzothiazines and related compounds are dealt with by C. Brown and R. M. Davidson; these compounds have not been previously comprehensively reviewed. C. Avendafio and G. G. Trig0 review the chemistry of the hydantoins, a subject that has not been fully treated for nearly 30 years. Another biologically important group of compounds, the barbituric acids, of which the last definitive account appeared more than a quarter of a century ago, are brought up to date by J. T. Bojarski et al. Finally, H . Wamhoff discusses heterocyclic p-enamino esters, which are versatile synthetic building blocks. ALANR. KATRITZKY,FRS

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ADVANCES IN HETEROCYCLIC CHEMISTRY. VOL . 38

Recent Advances in the Chemistry of Dihydroazines ALEXANDER L. WEIS Department of Organic Chemistry. The Weizmann Institute of Science. Rehovot. Israel

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . I1. Scope and Limitations . . . . . . . . . . . . . . . . . . . . . 111. General Overview of Dihydroazine Chemistry . . . . . . . . . . . . . A. Nomenclature . . . . . . . . . . . . . . . . . . . . . . . 9.Structure . . . . . . . . . . . . . . . . . . . . . . . . . 1. Constitution and Stability . . . . . . . . . . . . . . . . . . 2. Molecular Geometry and Conformation . . . . . . . . . . . . . C. Preparation of Dihydroazines . . . . . . . . . . . . . . . . . . D . Tautomerism and Rearrangements . . . . . . . . . . . . . . . . 1. Amidinic Tautomerism . . . . . . . . . . . . . . . . . . . 2. Imine-Enamine Tautomerism . . . . . . . . . . . . . . . . E. Physicochemical Properties and Reactivity . . . . . . . . . . . . . IV. Dihydropyridazines . . . . . . . . . . . . . . . . . . . . . . A . General Comments . . . . . . . . . . . . . . . . . . . . . 9. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 1. Cyclization Methods . . . . . . . . . . . . . . . . . . . . 2. Cycloaddition Reactions . . . . . . . . . . . . . . . . . . 3. From Pyridazine and its Derivatives . . . . . . . . . . . . . . a. Addition of Organometallic Reagents . . . . . . . . . . . . . b . From 6-0xo-1,4,5, 6-tetrahydropyridazines . . . . . . . . . . . c. Reduction with Complex Hydrides . . . . . . . . . . . . . . d Electrochemical Reduction . . . . . . . . . . . . . . . . 4 . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . C. Tautomerism of Dihydropyridazines . . . . . . . . . . . . . . . D . Physicochemical Properties . . . . . . . . . . . . . . . . . . 1. Infrared Spectra . . . . . . . . . . . . . . . . . . . . . 2. Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . 3 Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . E. Reactivity. . . . . . . . . . . . . . . . . . . . . . . . . V . Dihydropyrimidines . . . . . . . . . . . . . . . . . . . . . . A. General Comments . . . . . . . . . . . . . . . . . . . . . 9. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 1. Cyclization Methods . . . . . . . . . . . . . . . . . . . . a. From a,/3 -Unsaturated Carbonyls . . . . . . . . . . . . . . b . From /3-Dicarbonyl Compounds . . . . . . . . . . . . . . c. Other Cyclizations . . . . . . . . . . . . . . . . . . .

3 6 6 6 9 9 12 15 18 19 21 22 23 23 23 23 27 32 32 35 37 37 39 39 40

.

40 41 41

.

1

44 45 45 45 45 45 53 54

.

Copyright 0 1985 by Academic Press Inc. All rights of reproduction in any form reserved.

ISBN 0-12-020638-2

2

ALEXANDER L. WEIS

2. From Pyrimidine Derivatives . . . . . . . . . . . . . . . . . a. Addition of Organometallic Reagents . . . . . . . . . . . . . b . Reduction with Complex Metal Hydrides . . . . . . . . . . . c. From 4-Halopyrimidines . . . . . . . . . . . . . . . . . d . Electrophilic Aromatic Substitution with Protonated Pyrimidines . . . e. Desulfurization of Pyrimidine-2( 1H)-thiones . . . . . . . . . . f . Electrochemical Reduction . . . . . . . . . . . . . . . . 3. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . C. Tautomerism of Dihydropyrimidines . . . . . . . . . . . . . . . 1. Tautomerism of 1.4- and 1,6-Dihydropyrimidines . . . . . . . . . . a. Structures of the Tautomers . . . . . . . . . . . . . . . . b . External Parameters Affecting the Rate of Tautomerism . . . . . . c. Description of NMR Spectra . . . . . . . . . . . . . . . . d . Kinetic Measurements . . . . . . . . . . . . . . . . . . e. Intra- and Intermolecular Mechanisms of Proton Transfer in Amidines . 2. Tautomerism of 1,2-Dihydropyrimidines . . . . . . . . . . . . . D . Physicochemical Properties . . . . . . . . . . . . . . . . . . 1. Infrared Spectra . . . . . . . . . . . . . . . . . . . . . 2. Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . 3. Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . 4. Crystal Structure . . . . . . . . . . . . . . . . . . . . . . E. Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . VI . Dihydro-1,2,3-triazines . . . . . . . . . . . . . . . . . . . . . VII . Dihydro-1,2,4triazines . . . . . . . . . . . . . . . . . . . . . A . General Comments . . . . . . . . . . . . . . . . . . . . . B. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 1. Cyclization Methods . . . . . . . . . . . . . . . . . . . . a . From N-Acylamino Ketones . . . . . . . . . . . . . . . . b. Other Cyclizations . . . . . . . . . . . . . . . . . . . 2. From 1,2,4-Triazine Derivatives . . . . . . . . . . . . . . . . a. Reduction of 1,2,4Triazines . . . . . . . . . . . . . . . . b. From 1,2,4-Triazines or 1,2,4Triazinones and Grignard Reagents . . . c. Electrochemical Reduction . . . . . . . . . . . . . . . . d . OtherMethods . . . . . . . . . . . . . . . . . . . . 3. From Other Heterocycles . . . . . . . . . . . . . . . . . . C. Physicochemical Properties . . . . . . . . . . . . . . . . . . 1. Infrared Spectra . . . . . . . . . . . . . . . . . . . . . 2. Ultraviolet Spectra . . . . . . . . . . . . . . . . . . . . 3. Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . D . Reactivity . . . . . . . . . . . . . . . . . . . . . . . . . VIII . Dihydro-1,3,Striazines . . . . . . . . . . . . . . . . . . . . . A. General Comments . . . . . . . . . . . . . . . . . . . . . B. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . 1. From Nitriles . . . . . . . . . . . . . . . . . . . . . . 2. From Amidines . . . . . . . . . . . . . . . . . . . . . 3. From 1,3,5-Triazines . . . . . . . . . . . . . . . . . . . . 4. From 1,3,5-Oxadiazines. . . . . . . . . . . . . . . . . . . C. Tautomerism in Dihydro-1.3.5-triazines . . . . . . . . . . . . . . D . Physicochernical Properties . . . . . . . . . . . . . . . . . . 1. Infrared Spectra . . . . . . . . . . . . . . . . . . . . .

55 55 58

59 60 60 61 62 63 63 63 65 66 70 73 75 77 77 78 78 79 80 82 83 83 84 84 84 85

85 85 86 86 87 87 88 88

89 89 90 91 91 91 91 93 96 97 98 99 99

Sec. I]

DIHYDROAZINES

3

2. Ultraviolet Spectra and Photochromism . . . . . . . . . . . . . 100 3. Nuclear Magnetic Resonance Spectra . . . . . . . . . . . . . . 100 E. Reactivity. . . . . . . . . . . . . . . . . . . . . . . . . 101 IX. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . 102

I. Introduction Aromatic, six-membered, nitrogen-containing heterocyclic compounds (e.g., pyridines, diazines) have long been known, and their preparation, chemical and physical properties, and occurrence and function in biological systems have been extensively studied. At the same time, despite the large number of known reduced azines, their chemistry remains largely unexplored. Among the partially or totally saturated azines, particular attention has lately been given to the dihydroazines (DHA) which, as their name indicates, contain two additional hydrogens on the azine ring. They comprise a group of compounds that had previously been regarded primarily as unstable intermediates formed during azine synthesis. This lively interest in dihydroazines not only reflects the general renaissance of heterocyclic chemistry, but it is also the result of recent advances in theoretical, bio-, and medicinal chemistry. Of relevance to theoreticians, for example, is the ability to predict the structure, binding properties, chemical reactivity, etc. of dihydro compounds from a knowledge of the number and positions of the nitrogen atoms along with the disposition of double bonds within the DHA ring. New models for determining the relative stabilities of different DHA isomers open completely new approaches for predicting possible spontaneous isomerization of a derivative as well as its redox properties-a fundamental question of no less importance. Such quantum mechanical calculations also enable an evaluation of the degree of aromatic character in potential “homoaromatic” and “antiaromatic” isomers. From the biochemical point of view, dihydroazines and particularly those containing the 1Q-dihydropyridine moiety’-3 are of intense interest because of the presence of this group at the active site of “hydrogen transferring coenzyme” NADH (1) (reduced nicotinamide adenine dinucleotide). This nucleotide is a central participant in metabolic processes in living organisms, where it participates in the reduction of various unsaturated functionalities. In order to understand better the energetics and mechanism of NADH derivatives-both chiral and achiral-for use as NADH analogs. U. Eisner and J. Kuthan, J . Chem. Rev. 72, 1 (1972).

* J. Kuthan and A. Kurfurst, Ind. Chem. Eng. Prod. Res. Den 21, 191 (1982).

’ D. M. Stout and A. I. Meyers, J . Chem. Rev. 82,223 (1982).

4

ALEXANDER L. WEIS

[Sec. I

b

I

HO OH

In addition, biochemists are also interested in the 1,4-dihydroazine4*’ structure, present in several families of naturally occurring compounds, including the 1,5-dihydroflavins (2), which play a part in many biochemical processes, and the luciferins (3),which endow some interesting organisms with the property of bioluminescence. Pharmaceutical chemists, too, have evinced a keen interest in DHA chemistry, particularly the 4-aryldihydropyridines, which exhibit powerful vasodilating activities via the blocking of calcium channels and modifying movement of Ca2+ into and within the cell. The explosion in activity in this area of heterocyclic synthesis has produced an exponential growth in patent applications and papers and has led to the marketing of a new drug, nifedipine (4).6 Other active 4-aryldihydropyridine derivatives, such as nimodipine and nicardipine (cerebral vasodilators) and nitrendipine (antihypertensive), are presently under clinical trials.’ An excellent list of other practical applications of dihydropyridines has been collected by Kuthan and Kurfurst.2 The author originally intended this work as an overall survey of dihydroazine chemistry. However, the appearance in 1982 of excellent reviews of R. R. Schmidt, Angew. Chem., Int. Ed. Engl. 14,581 (1975).

’ W. Kaim, Angew. Chem., Int. Ed. Engl. 22, 171 (1983). ’

W. Vater, G. Kronenberg, F. Hoffmeister, H. Kaller, A. Meng, A. Oberdorf, W. Puls, K. Schlossmann, and K. Stoepel, Arzneim-Forsch. 22,1(1972). F. Bossert, H. Meyer, and E. Wehinger, Angew. Chem., I n t . Ed. Engl. 20,762 (1981).

Sec. I]

5

DIHYDROAZINES

R

H

H

O

I

H (3)

8 NO,

MeOOC Me

COOMe Me

H

(4)

d i h y d r ~ p y r i d i n eand ~ . ~dihydropyrazine8 chemistry has required some modification in order to avoid unnecessary duplication. This work, therefore, will not be an exhaustive treatise on the subject. It will summarize present knowledge and concentrate on the presentation of some important new trends and achievements in dihydroazine chemistry. We hope, in particular, to illustrate the generality and scope of many of the synthetic processes discussed. It is also our aim to point out how similarities in structure of various dihydroazines lead to similarities in their physical and chemical properties and how such common structural features can be utilized to predict properties of compounds that have not yet been obtained or studied experimentally. All readily accessible literature has been examined, including references which have appeared up to, and including, Volume 97 of Chemical Abstracts (December 1982), and some unpublished data (mainly from the author’s laboratory) have been included. Because of the subjectivity inherent in choosing material for inclusion in this survey, it is possible that some important contributions have been unintentionally overlooked, for which the author expresses his sincere apologies. G. B. Barlin, in “The Chemistry of Heterocyclic Compounds” (A Weissberger, and E. C. Taylor, eds.), Vol. 41, p. 344. Wiley, Chichester, 1982.

6

ALEXANDER L. WEIS

[Sec. 1II.A

11. Scope and Limitations Following the approach taken by Eisner and Kuthan in their review of dihydropyridines,' this article will incorporate only isolable or spectroscopically identified monocyclic dihydrodiazines and dihydrotriazines. We specifically exclude compounds containing exocyclic double bonds, i.e., particularly azine methenes, as well as 0x0-, thio- or iminodihydroazines (5a), which can be considered as tautomeric azines (5b),and hydroxy, mercapto, and amino DHA (6a), which can exist in the tautomeric tetrahydroazine form (6b).

X

= CH,,O,S,NH

a,b,c,d = C o r N

Particular attention will be given to those dihydroazines bearing no substituents on the ring nitrogen atom(@,which can undergo oxidation to the corresponding azines.

111. General Overview of Dihydroazine Chemistry A. NOMENCLATURE During the preparation of this review, minor inconsistencies in the nomenclature of dihydroazines were often encountered in the literature. Therefore, the author would like to present some systematic rules for numerating hydrogenated heterocycles, a convention which will be followed in this survey. (1) When the same heteroatom occurs more than once in a ring, the numbering is chosen to give lowest locants to the heteroatoms. (2) If there is still an ambiguity in numbering the dihydroazine, the lowest number is assigned to the heteroatom with the higher degree of saturation. (3) If there is still an ambiguity, numbering will be assigned such that the. extra hydrogens will have the lowest locants. According to these rules, the following names will be afforded to the possible isomeric dihydroazines.

Sec. III.A]

7

DIHYDROAZINES

1. Dihydropyridines:

2. Dihydropyridazines:

3. Dihydropyridimines:

H

H

H

4. Dihydropyrazines: H

1,2(101)

5. Dihydro-1,2,3-triazines:

1,4-

2,3-

2,5-

(lob)

(I&)

(W

8

ALEXANDER L. WEIS

6. Dihydro- 1,2,4-triazines: H

H

H

H

n H

8. Dihydro- 1,2,3,4-tetrazines:

9. Dihydro-1,2,3,5-tetrazines:

H

[Sec. 1II.A

Sec. III.B]

DIHYDROAZINES

9

10. Dihydro-1,2,4,5-tetrazines:

B. STRUCTURE 1. Constitution and Stability One can formally divide isomeric dihydroazines (see Section II1,A) into two groups of compounds: those in which a lone pair of p electrons from a nitrogen can conjugate with the four 7c electrons of the diene portion of the molecule, e.g., cyclic enaminesg (structures A, B, C , and D), and those in which it cannot, e.g., cyclic imines (structures E, F, and G). H

where a,b,c,d = C or N

The isosteric and isoelectronic nature of the various molecules formed by permuting the carbon and nitrogen atoms of each individual type leads to “families” of compounds whose members show certain similarities in physical and chemical properties. Common experience in the field, for example, indicates that cyclic enamines of types A and B are usually more stable than 0.Cervinka, in “Enamines:Synthesis,Structure and Reactions” (A.G. Cook, ed.), Chapter 7, p. 253. Dekker, New York, 1969.

10

ALEXANDER L. WEIS

[Sec. 1II.B

cyclic imines E, F, and G (in contrast to acyclic compounds”), whereas C and D are less stable. These differences may be explained in terms of aromaticity,’ that is, stabilization due to cyclic electron delocalization within the planar ring depends on the number of, and the orbital interaction between, the participating electrons. The cyclic p conjugation present in structures A and B produces a six-electron delocalized system, which obeys the Hiickel4n + 2 rule, and is potentially homoaromatic.’2 The degree of aromaticity exhibited by these compounds will depend on the energies of the orbitals containing the p lone pair and the system as well as, obviously, the degree of planarity of the molecule. On the other hand, the analogues of C and D exhibit potential antiaromaticity’ as a consequence of cyclic conjugation of a total of eight ( 4 4 electrons, giving rise to antiaromatic destabilization. Thus the ~ a l c u l a t e d ’ ~ antiaromatic destabilization for the unsubstituted, heteroconjugated 1,4dihydropyrazine (lob) is about 2.9 kcal mol-’, much smaller than that observed for the analogous isoconjugated system. The only stable parent compound isolated to date is 1,2-dihydro-1,2,4,5-tetrazine(16a);’ 1,4dihydropyridine (7b)16was isolated and found to be extremely unstable, and while tautomeric 1,4-(9b) and 1,6-dihydropyrimidine (9c) were prepared,’ they could be identified only by spectroscopic means. The majority of other parent compounds (possible isomers) were investigated theoretically. Thus energies of all possible unsubstituted dihydropyridines (7a-e) were calculated via MIND0/3,’* as well as ab initio 4-31G technique^.'^ Indeed, the unsubstituted 1,4-dihydropyridine (7b) was predicted to be the most stable isomer. Experimental confirmation of these calculations was provided by Fowler,” who prepared the stable l-methyl derivatives of 7a and 7b and found the 1,4 derivative to be more stable than the 1,2 derivative by 2.29 f 0.01 kcal mol-’. He suggested the increased stabilities of the former compound to be due to “favorable electronic interactions” (hyperconjugation or homoaromaticity). Gaussian 70 ab initio calculations of the energy of unsubstituted dihydropyrimidines (9a-e)’l yielded the following order of stability: 9c > 9b > 9a > 9d > 9e. These results agree with the experimentally observed behavior of

’

lo

P. W. Hickmott, Tetrahedron 38,1975,3363 (1982).

’’ P. J. Garratt, “Aromaticity,” McGraw-Hill, London, 1971.

L. A. Paguette, Angew. Chem., I n t . Ed. Engl. 17, 106 (1978). R. Breslow, Angew. Chem., I n t . Ed. Engl. 7,565 (1968); Acc. Chem. Res. 6,393 (1973). l4 N. Trinajstic, J . Mol. Struct. 8, 236 (1971). C. Grundmann and A. Kreutzberger, J . Am. Chem. SOC.79,2839 (1957). l 6 T. Koenig and H. Longmaid, . I Org. . Chem. 39,560 (1974). A. Weis and D. Zamir, unpublished results (1983). N. Bodor and R. Pearlman, J . Am. Chem. SOC. 100,4946 (1978). l 9 S. Bohm and J. Kuthan, Collect. Czech. Chem. Commun. 46,2068 (1981). 2 o F. W. Fowler, J . Am. Chem. SOC.94, 5926 (1972). A. L. Weis and U. Degan, unpublished results (1982). I’

’’

Sec. III.B]

11

DIHY DROAZINES

these compounds. The total energies of the parent molecules 4,5-dihydropyridazine (8f) and 1,4-dihydropyridazine (8b) were also calculated by the Gaussian 70 and MIND0/3 techniques.” The importance of carrying out more sophisticated Gaussian 70 calculations (STO-3G, STO-6G, STO-4-3 1G) was confirmed by this pair of compounds: 8f was found to be slightly more stable at lower levels of calculation, while 8b was significantly more stable at higher levels. Despite a paucity of theoretical calculations, those available agree with experimental data. Thus cyclic enamines of types A and B are the best known compounds among the DHA. In addition, when the energy difference between the imine and enamine is large, corresponding cyclic imines E, F, and G usually isomerize spontaneously via proton transfer to the theoretically more stable A or B. When it is small, the two isomers exist in tautomericequilibrium. Tautomerism can also be achieved by proper selection of solvent and substituents. (For a summary of isomerism and tautomerism in DHA, see Section 111,D.)On the other hand, antiaromtic DHA (C and D) are usually less stable than the corresponding cyclic imines. With regard to cyclic imines E, F, and G, only those containing disubstitution have so far been isolated because geminal disubstitution prevents the above-mentioned isomerization from taking place. For types C and D, stabilization can also be achieved by gem disubstitution, but for these compounds substituents on the nitrogen (1) stabilize as well. Moreover, by comparison of all available data on DHA, one can conclude that, in general, p substitution of cyclic enamines A, B, C, and D by electronwithdrawing substituents, such as COR, CO,R, CN, NO,, and S02R, enhances their chemical stability as has been observed, for example, in “Hantzsch dihydropyridines” (17a), 5-functionalized pyrimidines (17b), and pyridazine (17c).

(174

(17b)

(17~)

Similarly, introduction of electron-donating substituents such as NR, ,SR, or OR in the a or y position of usually unstable cyclic imines E, F, and G enhances chemical stability and enables these compounds to be easily isolated in each DHA family, for instance, 3,4-dihydropyridines (18a), 2,s-dihydropyrimidines (18b), 4,5-dihydropyrimidines (18c), and 4,5-dihydropyridazines (18d). 22

W. L. Hedges, Ph. D. Thesis, University of New Orleans (1981). J. Baker, W. Hedges, J. W. Timberlake, and L. M. Tzefomas, J . Heterocycl. Chem. 20,855 (1983).

12

[Sec. 1II.B

ALEXANDER L. WEIS

2. Molecular Geometry and Conformation The molecular geometry of a number of solid DHA have been determined by X-ray diffraction crystallography. Naturally, the majority of structures are available for the most stable dihydropyridines (7a,b).’ These data indicate that, generally, the ring systems of 1,Zdihydropyridines show slight deviations from strict planarity as well as significant conjugation between the double bonds and nitrogen lone pair of electrons. The conformations of the extensively studied Hantzch’s lY4-dihydropyridineswere found to be planar, boatlike, or envelopelike, depending on ring substitution.’ Recent X-ray examinations of the molecular structures of different dihydropyrimidinic isomers were carried out primarily to obtain unambiguous structural assignments. Of course, important information was also obtained regarding bond lengths and angles, i.e., conformation of these molecules in the solid state. Thus an X-ray diffraction study of 4,6,6-trimethyl2-phenyldihydropyrimidine (19)23 clearly showed the 1,6-dihydro structure (19b),where, similar to the 1,2-dihydropyridinesYslight deviations from strict planarity were observed (N-1 and C-6 atom out of ring), while the lone pair of N-1 undoubtedly takes part in conjugation with the double bonds. Me

Me‘

..

H

H

(19~

(209)

H (214

The structure, geometry, and conformation of solid 2,4-diphenyl-6.~~ methyldihydropyrimidine (20) were determined by X ray d i f f r a ~ t i o nThe analysis has shown clearly that the crystalline form of this compound has a 1,Cdihydro structure (20a)with a nonplanar ring. Atoms N-1 and C-4are out 23 24

A. L. Weis and F. Frolow, Heterocycles 19,493(1982). A. L. Weis and F. Frolow. Chem. Commun., 89 (1982)

Sec. III.B]

DIHY DROAZINES

13

of the plane formed by the two double bonds C-2=N-3 and C-5=C-6 by about 0.10 and 0.25 A, respectively, thus forming a ring with a flat-boat conformation. Particularly interesting data were obtained from the X-ray (21a)in which only diffraction analysis of 4,6-diphenyl-lY2-dihydropyrimidine C-2 and C-5 were found to be out of plane and N-1 was nearly coplanar. The N-1 showed a high degree of conjugation with the double bonds, but does not possess the structure of a homoaromatic specie^.^' This structure is very similar to that formed for dihydrotetrazine 22, in which only C-6 is out of plane. The distance between the two nitrogens in 21a precludes the existence of N-N interaction, and therefore also of “homoaromaticity.” Van der Plas and co-workers26 elucidated the crystal structure of homoaromaticZ76-ethyl-3-phenyl-1,6-dihydro-1,2,4,5-tetrazine (22) by X-ray structure analysis. The molecule is in a boat conformation with C-6 and C-3 pointing upward, with dihedral angles of 49.3 (0.51 A) and 26.7“ (0.26 A), respectively. N-1 was found to be sp2 hybridized, and the N-1-N-2, N-2C-3, C-3-N-4, and N-4-N-5 bond distances were intermediate between those of single- and double-bond lengths. These intermediate bond lengths are in agreement with delocalization of the ‘IL electrons over this ring. It is striking that the character of the N-1-N-2 (1.32 A) bond is so aromatic. Me I

(22)

(23)

Olofson and co-workers2*obtained evidence for homoaromaticity of the

1,1,4-trimethyl-1,4-dihydro-1,2,4,5-tetrazinium cation (23) from a crystalstructure determination. The quaternary nitrogen N- 1 is tetrahedral, causing the ring to assume the boat shape. There is evidence for substantial delocalization of the N-4 electron pair (hybridization between sp2 and sp3), whereas N-1 is 0.51 A,while N-4 is only 0.26 A above the N-2-C-3-N-5C-6 plane. It should be noted that the crystal structures of 22 and 23 have remarkable similarities. Both molecules are in the boat conformation with their prows twice as high as their sterns. Also, carbons occupy these apices in L. Weis, F. Frolow, and R. Vishkaucan, unpublished results (1983). C. H. Stam, A. D. Counotte-Pottman, and H. C. van der Plas, J. Org. Chem. 47,2856 (1982). A. Counotte-Pottman, H. C. van der Plas, and A. van Veldhuizen, J. Org. Chem. 46, 2138

z’ A. 26

*’

(1981). 28

D. H. Hoskin, G . P. Wooden, and R. A. Olofson, J. Org. Chem. 47,2858 (1982).

14

ALEXANDER L. WEIS

[Sec. 1II.B

22, while nitrogens occupy these sites in 23. Molecule 23 is slightly flatter than 22, and subsequently the increased “boat character” of the latter molecule is reflected in a decreased rate of ring inversion from the one boat form to the other. It should be noted that all attempts to decrease ring inversion in 1,2dihydropyrimidine (21) under the conditions reportedz4 failed. The reason for this failure probably lies in the close proximity of C-2 to the plane, which acts to increase the rate of inversion. Streitwie~er,~’ employing molecular orbital calculations, has predicted the thermodynamic destabilization brought about by placing the last two electrons of l,4-dihydropyrazine in antibonding orbitals. However, the degree of antiaromaticity must depend critically upon the conformation of the dihydropyrazine ring, which controls the ability of the nitrogen lone pairs to interact with the K system. The degree of antiaromaticity may be controlled by the substituents on the dihydropyrazine ring, and the reason for unexpected stability of some potentially antiaromatic 1,Cdihydropyrazines can result only from a special conformation opposing cyclic delocalization of the eight electrons. This was confirmed by X-ray structural analysis of 1,4-bis(p chlorophenyl)-2,6-diphenyl-1,4-dihydropyrazine (24).30 The four carbon atoms of the dihydropyrazine skeleton form a plane, while the two nitrogen atoms N-1 and N-4 are arranged at different distances above this plane, forming a quasi-boat conformation. The position of the aryl group on N-1 apparently leads to separation of the electronic interactions, yielding a six-n-electronic delocalized homoaromatic system (C-2-C-3-N-4-(2-5C-6 plane) and an almost orthogonal lone pair on N-1. According to Schmidt: this structural observation supports the notion that six-membered, formally antiaromatic ring systems can counteract electronic destabilization by assuming a conformation of substituents, which substantially reduces or eliminates delocalization of the eight K electrons. Moreover, this substituent control over stability of 1,4-dihydropyrazinesshould be more important than the deviations of the cyclic skeleton from planar it^.^'.^' To confirm the structures of NaBH, reduction products of 1,2,4-triazines, Japanese workers recently published an X-ray study, showing that the product has the 2,Sdihydro structure (25). The dihydrotriazine ring was found to take the boat conformation, which, because of the delocalization of the K electrons and lone-pair electrons of N-2, was significantly squashed.33 A. Streitwieser, Jr., “Molecular Orbital Theory for Organic Chemistry,” p. 275. Wiley, New York, 1961. 3 0 I. J. Sterowski, Cryst. Struct. Commun. 4, 21 (1975). 3 1 J. W. Lown, M. H. Akhtar, and R. S. McDaniel, J. Org. Chem. 39, 1998 (1974). 32 H. Kohn and R. A. Olofson, J . Org. Chem. 37, 3504 (1972). ” H. Ayato, I. Tanaka, T. Yamane, T. Ashida, T. Sasaki, K. Minamoto, and K. Harada, Bull. Chem. Soc. Jpn. 54,41 (1981). 29

Sec. III.C]

15

DIHYDROAZINES R I

I

R (24) R = p-CIC6H4

(25)

c. PREPARATION OF DIHYDROAZINES The various methods of synthesizing dihydroazines fall broadly into two main divisions: cyclizations and modification of a preexisting azine nucleus. Besides these two main types, some more specific approaches have also been designed. As will be shown below, the cyclization methods involve mainly the following combinations of fragments: (5+1)

(4+2)

(3+3)

(2+1+2+(1))

(3+1+(1)+1)

The most common approach to obtain dihydroazines usually involves Schiff-base chemistry. For example, (4 2) combinations have found wide application in the preparation of 4,5- (8f)and 1,4- (8b) dihydropyridazines by condensation of 1,Cdiones with hydrazine (Scheme 1).

+

oH

SCHEME1

16

[Sec. 1II.C

ALEXANDER L. WEIS

On the other hand, 2,3-dihydropyrazines (10c) are formed most readily by a condensation of 1,Zdiones with bisamines (Scheme 2). H

0

H7N

0

HZN

0 NH2

HO

H

SCHEME 2

The most direct synthesis of 1,Cdihydropyridines (7b) utilizes a procedure with either ( 5 + l), (3 + 2 + l), or (2 + 1 + 2 + (1)) fragment combination. The latter represents the widely used classical Hantzsch's synthesis, which combines two molecules of an active a-methylenic carbonyl compound, an aldehyde, and an ammonia source (Scheme 3). R2

I

CH

,:,,,

HO

The reaction of easily available a,P-unsaturated carbonyl compounds and amidines is an attractive (3 + 3) combination for the preparation of tautomeric 1,4- (9b)and 1,6- (9c) dihydropyrimidines (Scheme 4).

Sec. III.C]

17

DIHYDROAZINES

H

I SCHEME 4

We chose the four above-mentioned reaction schemes specifically to indicate that, despite the wide use of these synthetic approaches and the relatively well-known chemistry of Schiff bases, they actually remain widely unstudied. For over a century, the mechanisms by which these reactions were suggested had no experimental justification. It is easy to note the similarities in formation of the intermediate cyclic N,O hemiacetals (carbinolamines) (26a-d). These compounds are usually found to be relatively stable and i ~ o l a b l e(see ~ ~ also Section V,B,l,a), in contrast to the unstable acyclic carbinolamines. The dehydration step also requires further investigation because the initial dehydration product may be stable, it may exist in tautomeric equilibrium, or it may be converted spontaneously to the more stable isomer ring, depending on the relative stabilities of the various isomers. If a detailed mechanism for these reactions is known, control of experimental conditions can be used to direct reaction products and improve yields. As the name suggests, dihydroazines may be, and some actually are, formed by the addition of two hydrogens to the azine nucleus. According to Evans,35 reductions of organic species can be classified according to the active entities involved: 1. Hydrogen atoms are implicated or thought to be implicated in (a) catalytic reduction, (b) electrochemical reduction at a low-overvoltage electrode, (c) photochemical reduction, (d) reduction involving complex metal 34 35

K. L. Marsi and K. Thorre, J . Org. Chem. 29,3102 (1964). R. F.Evans, in "Modern Methods in Organic Chemistry"(C. J. Timmons,ed.),Chapter 1. Van Nostrand-Reinhold,Princeton, New Jersey, 1969.

18

ALEXANDER L. WElS

[Sec. 1II.D

hydrides derived from Group IVB metals, (e) diimide reductions, and (f) homogeneous reductions by dihydro derivatives of Group VIII metals. 2. Hydrogen is transferred as hydride ion in (g) reduction involving complex metal hydrides containing boron or aluminum, (h) homogeneous hydrogenation involving certain monohydride complexes of Group VIII metals, and (i) hydrogen transfer from one substrate to another. 3. Finally, hydrogen is transferred as protons in (j) reduction brought about by dissolving metals, (k) electrochemical reduction at a high-overvoltage electrode, and (1) reduction, the first stage of which is attack by an anion. However, it is symptomatic of the present state of DHA chemistry that only a few of the possible reductions have been used systematically to produce azine compounds. Reduction chemistry is best known for the pyridine series. The addition of organometallic reagents to six-membered nitrogen heterocyclic aromatic compounds (azines) is fairly general, leading to the corresponding dihydro derivatives. It should be noted, however, that organomagnesium compounds are less reactive toward these substrates, as shown by the requirement of more vigorous reaction conditions. Therefore, their use is often subject to complications, and they generally give results inferior to those of organolithium compounds. Both organolithium and organomagnesium compounds add to a,/?-ethylenimine fragment of azines. In general, both 1,2- (or 1,6-) and 1,Caddition occur, but under kinetic control organolithium compounds show a greater tendency to 1,Zaddition than do organomagnesium compounds. However, the reversibility of 1,Zaddition can lead to the eventual formation of 1,Cadducts under thermodynamic cont r 0 1 . ~Certainly, ~ many less general methods are found in the literature.

D. TAUTOMERISM AND REARRANGEMENTS Existence of a variety of isomeric DHA (Section II1,A) with different (ground-state energy) stabilities gives rise to various isomerization processes, which are usually reversible or irreversible migrations of a group from one site to another. The study of these isomerizations is still in its infancy. What is known will be presented below. The thermal suprafacial [1,3]-alkyl shift of 1,4-dialkyl-1,4-dihydropyrazinesreported by Lown and c ~ - w o r k e r s ~ ~is, ~ ’ - ~ ~ the only known migration of a group different from hydrogen in the DHA J. B. Wakefield, in “Comprehensive Organometallic Chemistry” (G.Wilkinson, ed.), Vol. 7, p. 15, Pergamon, Oxford, 1982. 3’ J. W. Lown and M. H. Akhtar, Chem. Commun., 829 (1972). 38 J. W. Lown and M. H. Akhtar, Chem. Commun., 51 1 (1973). jgJ. W. Lown and M. H. Akhtar, Tetrahedron Lett., 179 (1974). 36

Sec. III.D]

DIHYDROAZINES

19

series. Thermal isomerizations, including hydrogen transfer in DHA, may be divided into those involving, formally, either [1,3]- (amidinic and imineenamine tautomerism) or [1,q-hydrogen shifts. In the chemical literature it is common practice to classify hydrogen migrations as either rearrangements or tautomerisms, depending on their kinetic and thermodynamic parameters, the former being reserved for irreversible or slow processes, while the latter are used to describe fast reversible exchanges. Minkin and co-workers have provided criteria for distinguishing between tautomerism and rearrangement, which are summarized in Eqs. (1) and (2).40 AGO,, < 6 kcal mol-’

(1)

< 25 kcal mol-’

(2)

Equation (1) is dictated by the sensitivity of current techniques to detect a minor tautomer in an equilibrium mixture. Equation (2) serves to define tautomeric rearrangements as those transformations in which the lifetimes of the isomers are too short to enable the preparative separation of the two forms. Obviously, the above criteria should be regarded as no more than guidelines. Nevertheless, they do form a useful basis for distinguishing tautomeric reactions from rearrangements.

1. Amidinic Tautomerism The prototropic tautomerism of compounds containing an amidine moiety has been studied extensively.4143 However, the data obtained on this type of equilibrium are rather qualitative and have not been explored systematically. The difficulties encountered in this work stem primarily from the common experience that proton transfer between electronegative atoms, such as nitrogen, is very fast.43,44 The structure of an amidinic compound has usually been given in the literature as a presumed, predominant tautomer, without supporting evidence for a definitive structure. According to the recently published “systematization” of tautomeric pr0cesses,4~ the amidinic tautomerism is related to isodesmic [1,3]-sigmatropic tautomerism and, in the case of prototropism, 40

V. I. Minkin, L. P. Olekhnovich, and Y. A. Zhdanov, Acc. Chem. Res. 14,210 (1981).

41

G. Schwenker and K. Bod, Pharmazie 24,653 (1969).

A. R. Katritzky and J. M. Lagowski, Adu. Heterocycl. Chem. 1, 311; 2, 1 (1969). J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, Adv. Heterocycl. Chem., Suppl. 1 (1976). 44 A. J. Kresp, Acc. Chem. Res. 3,354 (1975). 45 N. S. Zefirov and S. S. Tratch, Chem. Scr. 15,4 (1980). 42

43

20

[Sec. 1II.D

ALEXANDER L. WEIS

may be expressed by the following general scheme: \

N

\

H

I l l

,C-N

\

1

N-H

,C=N

\

Three classes of tautomeric equilibria can be distinguished according to the molecular structure of the amidinic compounds:

1. Acyclic:

I

I

R

R

2. Semicyclic: H

3. Cyclic or annular: H\

H'

Among the many publications on tautomerism of heterocyclic compounds, annular tautomerism is one of the most widely studied, despite the strong hydrogen bonding and usually low activation energies, which complicate precise quantitative measurements. Most efforts were devoted to investigation of the amidinic tautomeric equilibrium in imidazoles or cyclic systems containing the imidazole fragment moiety (histidine, purine, etc). Experimental evidence concerning annular tautomerism in six-membered cyclic amidines is very limited. Moreover, in the dihydroazine series no data were available until recently. X-N

"J

X-NH

= (N+J

H X=CorN

Discovery of the amidinic tautomerism series of 1,4- (9b) and 1,6- (9c) dihydropyrimidines (Section V,E) and 1,2- (13a) and 1,4- (13b) dihydro-1,3,5-

Sec. III.D]

21

DIHYDROAZINES

triazines (Section VIII,C), together with the ability to observe individual tautomers and measure their concentrations and kinetic parameters under different experimental conditions by NMR, IR, and other instrumental methods, expands the horizons of proton-transfer chemistry. Moreover, it is to be expected that amidinic tautomerism could serve as a convenient model for investigating, in general, the factors governing tautomerism in cyclic molecules and could also be used for comparative studies on the factors controlling corresponding tautomeric effects in noncyclic analogues.

2. Imine-Enamine Tautomerism Imine-enamine tautomeric equilibrium was observed in different substituted dihydroazines by NMR spectroscopy. Pinson and c o - ~ o r k e r sre~~ ported, for example, that a solution of 3,6-diphenyl-l,2-dihydropyrazine(27b) in CDCI, contains a tautomeric mixture of 2,5- (27a)and 1,2- (27b)dihydro derivatives in the ratio 30:70. Ph

n",s'"- fyPh Ph

H

(27s)

(27b)

This result shows that the two isomers are in thermodynamic equilibrium. Moreover, when deuterated acetone is added to the chloroform solution, equilibrium is displaced toward the 1,Zdihydro derivative (27b). A similar type of tautomerism was found in a series of dihydropyridazines (see Section IV,C) and dihydropyrimidines (see Section V,C,2). For example, on the basis of NMR measurements in CDCI,, it has been shown that 3,6diphenyl-4,5-dihydropyridazine(28a)exists in tautomeric equilibrium with the corresponding 1,4-dihydro compound (28b)in the ratio 1:8.

(284

(Db)

Furthermore, 'H-and l3C-NMR investigations of 1,2-dihydropyrimidine 21a in CDCI, have demonstrated the existence of tautomeric equilibrium with the corresponding 2,5-dihydro isomer (21b) in the ratio 2: 1 (See Section V,C,2). 46

J. Armand, K. Chekir, and J. Pinson, Can. J . Chem. 52,3971 (1974).

22

[Sec. 1II.E

ALEXANDER L. WEIS

Imine-enamine equilibrium depends on the difference between the two isomers, solvent polarity, and substituent effects on the dihydroazine ring; and according to the definition of tautomerism, where the energy difference is not overwhelmingly large [Eq. (l)], tautomeric equilibria are observed experimentally for various dihydroazines. Whereas in the case of large energy differences, fast rearrangement to the thermodynamically more stable isomer occurs, for instance, the rapid transformation of 4,5-dihydropyrimidines to tautomeric 1,4- and 1,6-dihydropyrimidines (see Section V,C, 1) or the formation of 1,4-dihydropyridazines by cycloaddition to 1,2,4,5-tetrazines (see Section IV,B,2). Some other examples of rearrangements have been published. 2,3Dihydropyridazines are rearranged thermally or by base to the 1P-dihyd1-0 isomer^.^' Upon heating, the 5,6-dihydropyridazine derivative undergoes a thermally allowed suprafacial [1,5]-sigmatropic hydrogen rearrangement to give the 1,6-dihydro deri~ative.~'Moreover, a [1,514gmatropic hydrogen rearrangement of unsymmetrically substituted 1,2-dihydropyrimidines was reported.49 Undoubtedly, the above-mentioned examples are just a start toward investigating migrations in dihydroazines. Detailed research of these processes will certainly provide a deeper understanding of the problems of tautomerism and rearrangements as a whole as well as of the energetics, reactivity, and mechanisms of the formation of a variety of dihydroazines.

E.

PHYSICOCHEMICAL PROPERTlES AND

REACTIVITY

Most of the available data are found in the experimental sections of the original preparative work, giving the standard IR, UV, and NMR spectral data. To date no systematic study of the physical properties have been undertaken, nor have any measurements of theoretical interest been carried out, such as photoelectron emission, mass spectrometry, and electrochemical determinations. E. E. Schweizer and C. M. Kopay, J . Org. Chem. 37, 1561 (1972). P. De Mayo and M. C. Usselman, Can. J . Chem. 51, 1724 (1973). 49 S. Hoffmann and E. Muehle, 2. Chem. 9.66 (1969).

47 48

Sec. IV.B]

DIHYDROAZINES

23

Since most of these compounds have only recently been prepared, there has been little time to study their chemical behavior.

IV. Dihydropyridazines A. GENERAL COMMENTS Although no review dedicated entirely to dihydropyridazine chemistry has yet appeared, short surveys of synthetic approaches can be found in all reviews of pyridazine c h e m i ~ t r y . ~Naturally, ~ - ~ ~ this information is presented from the point of view of chemists desiring to synthesize pyridazine rather than as an account of dihydropyridazine chemistry per se, and the pertinent material is, therefore, scattered throughout the reviews and not presented systematically. Since those dihydropyridazines with unsubstituted ring nitrogens exist almost exclusively as isomeric pairs 8f and 8b-often in tautomeric fast equilibrium with one another22-it has sometimes been difficult to differentiate clearly the chemistry of the 4,5-dihydropyridazines (8f) from that of the 1,4-dihydropyridazines (8b). Before the advent of modern spectroscopic techniques, workers found it difficult to assign a given tautomeric form to a particular dihydropyridazine. Thus many compounds originally reported as 4,5-dihydropyridazines may in fact exist predominantly as the corresponding 1,Cdihydro isomer. The reader should, therefore, note that in the following discussion, we have assumed that tautomeric forms of the various dihydropyridazines, as assigned by the original authors, are correct, unless subsequent data have contradicted their validity.

B. SYNTHESIS 1. Cyclization Methods

One of the most common and versatile methods for synthesizing dihydropyridazines is the condensation of saturated 1,Cdicarbonyl compounds with hydrazines (Scheme 1, Section 111,C). The first example of this type, provided by C ~ r t i u in s ~1894, ~ involves the reaction between diethyl 1,2-diacetylsuccinate and hydrazine hydrate. Following this work, several dihydropyridazines were synthesized by other early T. L. Jacobs, in “HeterocyclicCompounds” (R. C. Erdelfield, ed.), Vol. 6, p. 101. Wiley, New York, 1957. ’I M. Tisler and B. Stanovnik, Ado. Heterocycl. Chem. 9,211 (1968). M. Tisler and B. Stanovnik, Ado. Heterocycl. Chem. 24,363 (1979). ” T. Curtius, J . Prakt. Chem. [2] SO, 508 (1894).

’’

24

[Sec. 1V.B

ALEXANDER L. WEIS

at the beginning of this century. The results obtained by different authors gave rise to much controversy, since not all condensations of hydrazine with saturated diketones yield single products (mono- and bishydrazones, aminopyrroles, polymers, etc. can all be formed). Therefore, the reaction has been thoroughly investigated, especially with regard to reaction conditions, since different by-products can be produced under different reaction environments. Moreover, subsequent s t u d i e ~ ~ ’showed * ~ ~ that dihydropyrazine is formed only when equimolar amounts of diacetylsuccinic ester and hydrazine are used, and the originally proposed 4,Sdihydro structure (29a)for the reaction product has been corrected to the 1,Cdihydro structure 29b.60 COOEt

(294

COOEt

(29~

Over the following half century, investigators have reported the formation of two types of dihydropyridazines, depending on the structures of the starting materials. Thus 4,5-dihydropyridazines (8f) are produced in the reaction of hydrazine with di- and polysubstituted saturated 1,4dike tone^,^ while 1,4-dihydropyridazines (8b) are formed from the re-

’-’*

’‘ C. Paal and E. Dencks, Chem. Ber. 36,491 (1903). ’’A. Smith, Justus Liebigs Ann. Chem. 289,316 (1896). C. Paal and G. Kuhn, Chem. Ber. 40,4598 (1907). Bulow and H. Filchner, Chem. Ber. 41, 1886 (1908). ’13 G. Korshun, Chem. Ber. 37,2183 (1904). ” R. G. Jones, J . Am. Chem. SOC.78,159 (1958). ‘O W. L. Mosby, J . Chem. Soc., 3997 (1957). 6 1 G. Korshun and C. Roll, Gazz. Chim. Ital. 41, 186 (1911). 6 2 E. E. Blaise, C. R . Hebd. Seances Acad. Sci. 170, 1324 (1920). B. G. Zimmerman and H. L. Lochte, J . Am. Chem. SOC.60,2456 (1938). 64 S.Gapuano, Gazz. Chim. Ital. 68,521 (1931). ” W. Borshe and A. Klein, Justus Liebigs Ann. Chem. 548,74 (1941). 66 K. Alder and C. H. Schmidt, Ber. Dtsch. Chem. Ger. B 76,183 (1943). 6 7 H. Heller, R. Pasternak, and H. von Halban, Helu. Chim. Acta 29, 512 (1946). C. G. Overberger, N. R. Byrd, and R. R. Mesrobian, J . Am. Chem. SOC.78,1961 (1956). 69 C. L. Arcus and P. A. Hallgarten, J. Chem. Soc., 3407 (1957). 7 0 S.G. Cohen, S. H. Hsiao, E. Saklad. and C. H. Wang, J . Am. Chem. SOC.79,4400 (1957). ” R. G. Jones, J . Org. Chem. 25,956 (1960). 7 2 S. Fatutta, Ann. Chim. (Rome)51,252 (1961). 73 S. Fatutta, Ann. Chim. (Rome)52,365 (1962). 74 W. M. Williams and W. R. Dolbier, Jr., J . Am. Chem. SOC.94,3955 (1972). ’6

” C.

‘*

Sec. IV.B]

25

DIHYDROAZINES

action of a monosubstituted hydrazine with 1,4-diketones, lP-ketoaldehydes, or 1,4-dialdehyde~.~~-~~ However, not all reactions with saturated 1,4diketones proceed as simply as assumed. For example, acetonylacetone61.68 disproportionation leads to a mixture of the or 1,2-dibenz0ylethane~~~'~ corresponding pyridazine and tetrahydropyridazine. Different reaction conditions may also influence the reaction course. More recently, Russian workers have shown that l-alkyl-3,6-dimethyl-1,4dihydropyridazines(30)are produced in the condensation of acetonylacetone with alkyl hydrazines.81

Me

R' I

aR2

R (Ma) R = Me (Mb) R = Et

(a) R = Pr (3Od)R = Bu

I

R (31a) R

= Pr, (30b) R = t-Bu, (3Oc)R = i-Pr, (3Od)R = t-Bu, (3Oe)R = Me, (301) R = Pr,

R'

R' R'

R' R' R'

R2 = H = R2 = H = H, R2 = Me = H, R2 = Me = Me, R2 = H = Me, R2 = H =

The same authors" suggested a mechanism for the reaction of 1,4dicarbonyl compounds with monosubstituted hydrazines, which affords, depending on reaction conditions and structural factors, the mono- and bishydrazones, N-aminopyrroles, and 1,4-dihydropyridazines. Some relatively simple 1,4-dihydropyridazines (31) were prepared by condensation of monosubstituted hydrazines with succinic or levulinic aldehyde.'j At least two cases reporting the condensation of hydrazine with 1,4dialdehydes are known, Timberlake et a1.84*85found that unsubstituted 43dihydropyridazine (8f), produced from succinaldehyde and hydrazine, trimerizes to give 32 [Eq. (3)]. W. Schlenk, H. Hillemann, and J. Rodloff, Justus Liebigs Ann. Chem. 487,135 (1931). D. Desaty, 0. Hadzija, and D. Keglevic, Croat. Chem. Acta 37,227 (1965). 77 B. Helferich and 0. Lecher, Ber. Dtsch. Chem. Ger. B 54,930 (1921). 78 G. 0.Schlenk, Justus Liebigs Ann. Chem. 584,156 (1953). 'g M. Verzele and F. Govaert, Bull. SOC.Chim. Belg. 58,432 (1949). G. Westphal, 2. Chem. 9,339 (1965). K. N. Zelenin and J. Dumpis, Khim. Geterotsikl. Soedin. 7 , 1566 (1971). J. N. Zelenin and J. Dumpis, Zh. Org. Khim. 9, 1295 (1973). 8 3 K. N. Zelenin and J. Dumpis, Khim. Geterotsikl. Soedin. 7,400 (1971). 84 B. K. Bandlish, J. N. Brown, J. W. Timberlake, and L. M. Trefonas, J. Org. Chem. 38, 1102 7s

76

(1973). J. Dodge, W. Hedges, J. W. Timber1ake;and L. M. Trefonas, J . Org. Chem. 43,3615 (1978).

26

[Sec. 1V.B

ALEXANDER L. WElS

(32)

Schlenck and c o - ~ o r k e r showed s ~ ~ that tetrapheylsuccinaldehyde reacted with hydrazine to give 33. These authors did not report any trimerization of the dihydropyridazine. Apparently, the steric requirements of the phenyl groups preclude this eventuality.

Ph N’

(33)

The single example of the preparation of 1,2-dihydropyridazines (34) was reported by Zelenin and Dumpis,86 namely, the condensation of 1,2dialkylhydrazines with acetonylacetone [Eq. (4)]. Me

Me

I

R

(Ma) R = Me (34b)R = El

Other methods for synthesizing dihydropyridazines have been recorded but have not been generally applied. Hauser and c o - ~ o r k e r sfor ,~~ example, have reported the synthesis of dihydropyridazines 28a and 35 by an intramolecular coupling reaction [Eq. ( 5 ) ] . However, it has been shown that 35 exists in the

86

K. N. Zelenin, V. A. Nikitin, N. M . Anodina, and Z. M. Matvejeva, Zh. Org. Khim. 8, 1438 (1972).

” F.

E. Henoch, K. G . Harnpton, and C. R. Hauser, J . Am. Chem. SOC.91,676 (1969).

Sec. IV.B]

27

DIHY DROAZINES

1,4-dihydro form, probably because of more effective conjugation stabilization.22

&

phJ

Ph

N-N

- qLi Ph

2n-BuLi

Me Me Br-c-cpBr I I

I

Ph

R

p

P

h

+ MeXMe

I

Me Me

N-N

Ph

(5)

“/N

Me

Me

(35) R = Ph (28a) R = H

1,6-Dihydropyridazine(36a) was prepared in moderate yield by treatment of substituted a-imino ketones with vinyl triphenylphosphonium bromide [Eq. (6)1.88 +

+ CH, = CHPPh,Br\NH

-

or NaOMe/MeOH

Ph

‘N/\R

I

R

(36)

a. R = Ph b. R = Me C. R = C O , Et

(37)

The latter undergoes thermal (44%) or base-catalyzed (100%) rearrangement, affording 1,4-dihydropyridazine (37a). Severin et aLS9 found that l-phenyl-4-phenylhydrazono-2-buten1-01 undergoes cyclization to 1,2-dihydropyridazine (38) in the presence of p-toluenesulfonic acid.

I

OH

n+

Ph-CCH=CHCH=NN’ ‘Ph

I Ph

2. Cycloaddition Reactions The cycloaddition reaction of 1,2,4,5-tetrazineswith olefins developed by Carboni and Lindseygo represents a second major route to dihydropyridazines (Scheme 5). E. E. Schweizer, C. S. Kim, C. S. Labaw, and W. P. Murray, Chem. Commun., 7 (1973). 89

T.Severin, R. Adam, and H. Lerche, Chem. Ber. 108,1756 (1975).

90

R. A. Carboni and R. V. Lindsey, J . Am. Chem. SOC.81,4342 (1959).

28

ALEXANDER L. WEIS

[Sec. 1V.B

SCHEME 5

According to the mechanism proposed, the 1,Ccycloaddition (Diels-Alder reaction) of the diene part of the tetrazine to the dienophile (olefin) gives an unstable bicyclic intermediate, which spontaneously eliminates a molecule of nitrogen, forming a 4,5-dihydropyridazine, which in the absence of appropriate stabilization by gem disubstitution in positions 4 and 5, easily isomerizes to the thermodynamically more stable 1,4-dihydropyridazine (38). The structure of the latter intermediates were unambiguously proved using NMR.91*92 Noteworthy is the necessity to activate the tetrazines with electronwithdrawing groups and the olefins with electron-donating substituents for this reaction to occur. Thus tetrazines bearing electron-withdrawing substituents such as methoxycarbonyl, polyfluoroalkyl, and 2-pyridyl react with an olefinic component more rapidly than do those substituted with methyl or phenyl groups. Conversely, electron-rich olefins such as vinyl ethers show much greater reactivity than do electron-deficient olefins such as acrylonitrile and acrolein. Sauer and Heinrichsg3 found, for example, that N-morpholinostyrene (a very electron-rich olefin), ethylene, and acrolein showed relative reaction rates of 470,000:36,000:1, respectively, with 3,6-dicarbomethox ytetrazine. Because of the ease, speed, and quantitative course (in most cases) of the reaction of olefins with 3,6-dicarbomethoxy- 1,2,4,5-tetrazine, Nenitzescu et ~ 4 1 proposed . ~ ~ this reaction as a titrimetric method for the determination of these hydrocarbons. Carboni and Lindseygohave also pointed out the significant role played by steric restrictions, which may be important for the reactivity of dienophiles in the synthesis of dihydropyridazines. For instance, 2,3-dimethyl-2-butene (an electron-rich but sterically hindered olefin) reacts only with the polyfluoroalkyl substituted tetrazines 39a and 39b, giving correspondingly 4,5-dihydropyridazine 40ag5and 40b.90Even with these highly reactive tetrazines, the rate J. Sauer, A. Mielert, D. Lang, and D. Peter, Chem. Ber. 98, 1435 (1965). M. Avram, G. R. Bedford, and A. R. Katritzky, Red. Trau. Chim. Pays-Bas 82,1053 (1963). 9 3 J. Sauer and G. Heinrichs, Tetrahedron Lett., 4979 (1966). 94 M. Avram, J. G. Dinulescu, E. Marica, and C. D. Nenitzescu, Chem. Ber. 95,2248 (1962). ” M. G. Barlow, R. N. Haszeldine, and J. A. Pickett, J . C. S. Perkin I , 378 (1978). 92

Sec. IV.B]

29

DIHYDROAZINES

of cycloaddition is extremely slow, requiring about 2 weeks for the formation of M a . At the same time, however, tetrazine 39a reacts rapidly with styrene to give 1,Cdihydropyridazine 41.95

(4Oa) R = C F , (40b) R = CHFCF,

H (41)

The number of different tetrazines which have been used in this type of reaction (Scheme 5 ) is small and is essentially limited to the species already mentioned. However, a large number of olefins have been treated with these few tetrazines, yielding a large variety of dihydropyridazines. Cycloadditions are also known with diazoalkanes and related compounds. Diazomethane reacts with a cyclopropene, and the pyrazoline cycloadduct 42 is rearranged by acid to the dihydropyridazine 43.96*97 Similarly, the Me Me

A

MeOOC

COOMe

+CH,N,

-

MeOOC%Me

Me Me MeOOC N’ H

96

97

M. Franck-Neumann and C. Buchecker, Tetrahedron Lett., 2659 (1969). M. I. Komendantov and R. R. Bekmukhametov, Zh. Org. Khim. 7,423 (1971).

30

[Sec. 1V.B

ALEXANDER L. WElS

cycloadduct 44 is converted by alkali or acid to 3,5-diphenylpyridazine via the corresponding dihydropyridazine intermediates 45.98-' O0 H, FOOMe H COOMe

Ph

H (44)

(45)

Using thermolysis in benzene at 80°C for 12 hr, Padwa'" converted 3,6diphenyl-1,2-diazabicyclo[3.1.0]hexene to 1,6-dihydropyridazine 46; further heating of 46 resulted in the formation of 1,4-dihydropyridazine 28b. H

(46)

(2W

One of the products isolated by treatment of cyclopropene with methyl diazoacetate is dihydropyridazine 48,'" apparently formed via an unstable adduct (47) [Eq. (7)]. Me Me

Me Me

Me Me

I

H (47)

(48)

Diazomethane reacts in ether with the cyclopropenes 49 to yield the corresponding cycloadducts, which may be transformed by base catalysis or by chromatography on silica gel to 1,4-dihydropyridazine 50."' 98

M. I. Komendantov, R. R . Bekmukharnetov, and V. G. Novinskii, Zh. Org. Khim. 12, 801 (1976).

99 loo lo'

Io2

L. G. Zaitseva, I. B. Avezov, 0.A. Subbotin, and 1. G . Bolesov, Zh. Org. Khim. 11,1415 (1975). A. Padwa and H. Ku, Tetrahedron Lett., 1009 (1980). D. H. Aue, R. B. Lorens, and G . S. Helwig, J . Org. Chem. 44, 1202 (1979). M. Regitz, W. Welter, and A. Hartmann, Chem. Ber. 112, 2509 (1979).

Sec. IV.B]

31

DIHY DROAZINES 0 R 3 R4

$N?4y 'P(OMe), R2

-

N '

H

H

(50a) R 2 = H, R' = R4 = Me

(Sob) R2 = H, R3 = Me, R4 = t-Bu (5012) R 2 = R4 = Me, R' = H (5Od) R 2 = R3 = R4 = Me (5Oe) R 2 = H, R' = Ph, R4

=

Me

(51a) R 1 = PO(OMe),, R 3 = R4 = Me (5lb) R' = PO(OMe),, R 3 = Me, R4 = t-Bu ( 5 1 ~ )R 1 = CO,Et, R 3 = R 4 = Me (51d) R 1 = CO,Et, R' = Me, R4 = t-B

Analogously, use of the dimethyl ester of diazomethylphosphonic acid or the ethyl ester of diazoacetic acid instead of diazomethane gives the corresponding dihydropyridazine 51."' 1,2-Diaza-1,3-butadienesundergo thermal dimerization according to a [4 + 21 cycloaddition mechanism, affording 1,4-dihydropyridazine 52.86,'03

(52)

Aromatic diazonium salts undergo cycloaddition to dienes to produce Nsubstituted 1,6-dihydropyridazines 53 [Eq. @)I. Carpenter and co-workers lo4 have shown that 2,3-diazabicyclo C2.2.01 hex2-ene opens thermally to give unsubstituted 4,5-dihydropyridazine (8f)

lo3 lo4

S. Stickler and W. C. Hoffmann, Angew. Chem. 82,254 (1970). E. A. Wildi, D. van Engen, and B. K. Carpenter, J . Am. Chem. SOC.102,7994 (1980).

32

[Sec. 1V.B

ALEXANDER L. WEIS

-

R$+ArNiX-

(8) N' Ar

[Eq. (9)]. Under the conditions of their experiment, they found that a dimeric species (which could be characterized only partially because of its instability) was formed along with trimer 32.

3. From Pyridazine and its Derivatives

a. Addition of Organometallic Reagents. A third major route to . dihydropyridazines involves the addition of Grignard reagents or or-

ganolithium compounds to pyridazine or its derivatives. These reactions proceed via nucleophilic attack at the electron-deficient positions of the pyridazine ring, followed in many cases by 1,2-, 1,4-, or 1,6-addition, and further hydrolysis to give the desired dihydropyridazine. Letsinger and Lasco reportedlo5 that dihydropyridazines formed by the action of Grignard reagents or organolithium compounds on pyridazines are too unstable to permit characterization and thus underwent spontaneous aromatization. This reaction was reinvestigated by van der Stoel and van der Plas,'06 who managed to isolate the dihydropyridazines resulting from phenyllithium addition. However, these also proved too unstable for complete analysis.

r"'u-[0R+4zc.u"+fi

R

R

'NY

"A

N/

H

\

'N

'NN (54)

(55)

R. L. Letsinger and R. Lasco, J . Org. Chem. 21,812 (1956). R. E. van der Stoel and H. C. van der Plas, Red. Trau. Chim. Pays. Bas 97,116 (1978).

Sec. IV.B]

33

DIHYDROAZINES

On the basis of a detailed analysis of the resultant akylated and arylated pyridazines 54 and 55 produced by this reaction, Letsinger and Lasco found that the ratio of addition at position 3 to that at position 4 was sensitive to the metal in the organometallic reagentlo5: Grignard species attacked preferentially at position 4, while organolithiums produced the 3-substituted pyridazines. Both w ~ r k e r s ' also ~ ~ indicated ~ ' ~ ~ that the solvent has a marked effect upon orientation, noting that ether promoted formation of 54, while tetrahydrofuran increased the yield of 55. In addition, an interesting example of nucleophilic 1,2-and 1,4-addition of thienyllithium to pyridazine, with the formation of corresponding 1,6-(56) and 1,4-dihydropyridazine(57), has been published [Eq. (

,A&c 1.2-addition,

H I H

(56r) 2-thienyl (56b) 3-thienyl

(574 2-thienyl (57b) 3-thienyl

(58n) 2-thienyl

The product 1,4-dihydro-4-(2-thienyl)pyridazine (57) undergoes thermal rearrangement to 1,4-dihydro-3-(2-thienyl)pyridazine(58), which is induced by stronger stabilization conjugation between the two rings.

lo'

J. Bourguignon, C. Becue, and G . Queguiner, J. Chem. Res. Miniprint, 1401 (1981); J. Chem, Res., Synop., 104 (1981).

34

[Sec. 1V.B

ALEXANDER L. WEIS

The addition of organometallics to substituted pyridazines was studied '' Symmetrically 3,6-disubstituted pyridazines yield homoextensively. geneous 4-substituted products, but if the substituents differ, the formation of distinct 4- and 5-substituted products is expected. Thus Crossland and co-workers found that organolithium and Grignard reagents add to symmetrical 3,6-disubstituted pyridazines 59 at position 4 to 13+1l 7 For example, 3,6give dihydropyridazines 60 and 61 [Eq. (1 dimethoxypyridazine (59a) reacts with tert-butyl, phenyl, isopropyl, and ethyl Grignards to give the corresponding compound 60,'08 although the ethyl adduct is isolated only with difficulty.' l 3 When methyl Grignard is used in the reaction, 59a is recovered unchanged.

R

R'

R'

YK RA N / '

b. R = CI c.

+R

R

=

alkyl

(11)

d. R = aryl

H (59)

(60)

(61)

On the other hand, pyridazines 59b, c, and d were found to react with tertbutyl Grignard to give primarily the 1,4-dihydro compounds 61b, c, and d. 108,110.1 1 7 In unsymmetrical, 3,6-disubstituted pyridazines, the course of addition depends on both electronic and steric effects. Electronic considerations favor addition of organometallics such that the resultant negative charge is localized on the side of the more electron-withdrawing substituent. The formation of dihydropyridazines by the reaction of tert-butyl Grignard with trisubstituted pyridazines has attracted particular attention. 3,4,6Trichloropyridazine reacts with tert-butylmagnesium chloride, giving a I. Crossland, Acta Chem. Scand. 16, 1877 (1962). A. Christensen and 1. Crossland, Acta Chem. Scand. 17, 1276 (1963). ' l o L. Avellen and I. Crossland, Acta Chem. Scand. 23, 1887 (1969). ' ' I I. Crossland and H. Kofod, Acta Chem. Scand. 24,751 (1970). 'I2 1. Crossland, Acta Chem. Scand. 26,3257 (1972). ' I 3 I. Crossland, Acta Chem. Scand. 26,4183 (1972). 'I4 I. Crossland, Acta Chem. Scand. 22,2700 (1968). ' I 5 L.Avellen, 1. Crossland, and K. Lund, Acta Chem. Scand. 21, 2104 (1967). I. Crossland and L. K. Rasmussen, Acta Chem. Scand. 19, 1652 (1965). 'I7 I. Crossland, Acta Chem. Scand. 18, 1653 (1964). 1. Crossland and E. Kelstrup, Acta Chem. Scand. 22, 1669 (1968). A. K. Fateen and N. A. K. Shams, J . Chem. U.A.R. 11,301 (1968). I2O E. Kelstrup, Acta Chem. Scand. 23, 1797 (1969). F. G. Baddar, M. H. Nosseir, N. L. Doss, and N. N. Messiha, J.C.S. Perkin I, 1091 (1972).

lo'

Io9

Sec. IV.B]

35

DIHYDROAZINES

mixture of 4-tert-butyl- (62) and 4,5-di-tert-butyl-l,4-dihydroderivatives (63), together with a small amount of the trans-4,5-di-tert-butyl-4,5-dihydropyridazine (64) and other products [Eq. (12)].’14 The formation of 64 probably occurs by nucleophilic displacement of chlorine at position 4, followed by Grignard addition at position 5.

&-

CI

\

N’

+ CI

N’

H (62)

+ f-Bu,&

t-Bu& CI

N/ H

(12) N’

CI

(63)

(64)

The addition of tert-butyl Grignard to 4-tert-butyl-3,6-dimethoxypyridazine is even more interesting [Eq. (13)I.l O8 t-Bu &,Me

(67)

The product initially formed on workup with water is 4,5-di-tert-butyl-3,6dimethoxy- 1,4-dihydropyridazine (65). Upon treatment with acid, 65 converts rapidly to cis-4,5-di-tert-butyl-3,6-dimethoxy-4,5-dihydropyridazine (66), owing to the proton entering at the least hindered face of 65. The cis compound is then slowly transformed to the more stable trans isomer (67), presumably through equilibrium with 65. b. From 6-0~0-1,4,5,6-tetrahydropyridazines. The reaction of 60x0- 1,4,5,6-tetrahydropyridazineswith Grignard reagents or LiAlH, leads to dihydropyridazines. For example, mixing 6-0~0-3-styry1-1,4,5,6-tetrahydropyridazine with a three- to fourfold molar excess of certain aryl and a-naphthylmagnesium bromides has been reported to yield the 4,5-dihydropyridazine 68

36

[Sec. 1V.B

ALEXANDER L. WEIS

[Eq. ( 14)].'22 Similarly, the addition of phenyl Grignard to 6-0x0-3-phenyl1,4,5,6-tetrahydropyridazinegives the aromatic 3,6-diphenylpyridazine, presumably through the intermediacy of the dihydr~pyridazine.'~~~'~~

PhCH=CH f l\NH ' o

-[

PhCH=CH

fiLoH] \N/

flAr (14)

PhCH=CH

'N/

(68)

It was claimed that reaction of phenylmagnesium bromide with l-phenyl-625 oxodihydropyridazines affords 1,6-dihydropyridazines (69)[Eq. (191.' R

R

(69)

Aubagnac et al. reported the isolation of 1,4-dihydropyridazines 70 among the products of the reduction of 6-0x0- 1,4,5,6-tetrahydropyridazineswith LiAlHJEq. (16)].'26

R'

Po - .,Q,Y - OR

(16)

I

R (700) R = R' = Me (70b) R = Me, R' = Ph

(7k) (7Od) Iz2

Iz3 IZ4

R R

= =

Ph, R' = Me R' = Ph

A. Mustafa, W. Asker, A. H. Harhash, K. 4. Hoda, H. H. Jahine, and N. A. Kassab, Tetrahedron 20.531 (1964). F. G. Baddar, A. El-Habashi, and A. K.Fateen, J. Chem. Soc., 3342 (1965). F. G. Baddar, N. Latif, and A. A. Nada, J . Chem. Soc., 7005 (1965). M. A. F. El-Kaschef, F. M. E. Abdel-Megeid, and M. A. Michael, Egypt. J . Chem. 20, 117 (1977).

Iz6

J. L. Aubagnac, J. Elguero, R. Jacquier, and R. Robert, Bull. Soc. Chim. Fr., 2859 (1972).

Sec. IV.B]

37

DIHYDROAZINES

c. Reduction with Complex Hydrides. The majority of known 1,4- and 1,6-dihydropyridazines are highly substituted or have strong electronwithdrawing groups on the pyridazine ring. Simple 1,6-dihydropyridazines (71) have now been prepared from 1-methylpyridazinium salts and sodium borohydride.’ These dihydropyridazines gradually decompose in air at room temperature. If, however, the reduction is performed in the presence of methyl chloroformate, stable l-methoxycarbonyl-l,6-dihydrocompounds (72) were obtained, accompanied by a small amount of the 1,Cdihydro isomers (73) [Eq. (17)].127 H

R

n

R

flR’ -

’

H

\

R

N/

I

n

R

N’

R

+

flR‘ (17)

R

N’

I

Me

’

C0,Me

(71)

N/

I

C0,Me

(73)

(72)

Dihydropyridazines have also been produced by the reduction of aromatic pyridazines. For instance, the action of lithium aluminum hydride on the diethyl ester of 3,6-dimethylpyridazine-4,5-dicarboxylicacid produces 74 in addition to other compounds [Eq. (18)].’*’ COOEt EtOOC*e Me

N/

-

CH,OH E t O O C b M e Me

(18)

N’

I

H (74)

d. Electrochemical Reduction. Attention has been given to the electrochemical reduction of pyridazines. The following mechanism in Eq. (19) has been proposed by Klatt and Rouseff for the reduction of pyridazine in aqueous media.12’ The first reduction wave appears to be due to a twoelectron reduction with subsequent protonation of the reduced ring occurring on the nitrogens; a 1,2-dihydropyridazine is formed, which decomposes to nitrogen and an unsaturated hydrazino aldehyde that polymerizes. A second reduction wave is also observed, but it is reported to be due to the reduction of a ring-opened species. C. Kaneko, T. Tsuchiya, and H. Igeta, Chem. Pharm. Bull. 22,2894 (1974). G . Adembri, F. De Sio, R. Nesi, and M. Scotton, J . Heterocycl. Chem. 12,95 (1975). L. N. Klatt and R. L. Rouseff, J . Electroanal. Chem. Interfacial Electrochem. 41,411 (1973).

38

[Sec. 1V.B

ALEXANDER L. WEIS

H

H

Lund studied the electrochemical reduction of substituted pyridazines and reported that reduction of 3,6-diphenylpyridazine gave the 1,4,5,6-tetrahydro derivative 75.'" This is probably produced through the intermediacy of 43dihydropyridazine 28a since, according to Lund, neither the 1,2- nor the 1,4dihydro tautomers are expected to be reduced further under the reaction conditions used [Eq. (20)].

flph OHPh - flPh = Ze-+ZH+.

Ph

N'

Ph

N/ H

Ph

N/ H

Ph

H

(2W

(75)

On the other hand, 3-phenyl-6-dimethylaminopyridazine 76a is reduced smoothly to a 4,5-dihydropyridazine (77a). 3-Phenyl-6-methoxypyridazine (76b) and 3-methyl-6-chloropyridazine (76c) are also reduced to dihydro compounds but these are hydrolyzed to dihydropyridazinones (77b,c) at the low pH used in the reduction [Eq. (21)].13'

pH=4

(7611) R' = Ph, R 2 = N(Me), (76b) R1 = Ph, R' = OMe (7612) R ' = Me, R 2 = CI IJo

H. Lund, Faraday Discuss. Chem. Soc. 45, 193 (1968). H. Lund., Adu. Heterocycl Chem. 12,272 (1970).

Sec. IV.C]

39

DIHYDROAZINES

Electroreduction of pyridazines in the presence of acetic anhydride gives the acylated open-chain diamine~.'~'

4. Miscellaneous The synthesis of 3,6-dimethyl-6-n-butyl-5,6-dihydropyridazine (79),the first representative of 5,6-dihydropyridazines, using halogenation and dehydrohalogenation of the corresponding tetrahydro derivative (78), was described by de Mayo and U s ~ e l m a n n Upon . ~ ~ heating to 125"C, the degassed benzene or n-hexane solution of 79 undergoes a suprafacial [1,5]-sigmatropic rearrangement to yield quantitatively the 1,Qdihydro derivative (80) [Eq. (22)].

-

n-BuQMe Me

- OM' n-Bu Me

n-Bu

Me

H (78)

(79)

(22)

N' H

(80)

3,6-Diphenylpyridazine is reduced with sodium and ethanol, affording the 1,2-dihydro d e r i ~ a t i v e . ' Since ~ ~ 3,6-diphenyl-4,5-dihydropyridazineis more stable than the isomeric 1,Zdihydro compound, the latter is isomerized in the presence of alkali to the 4,Sdihydro compound.'34 The 1,2diethoxycarbonyl-l,2-dihydropyridazineis formed by selenium dioxide oxidation'35 or via allylic bromination-dehydrobr~mination~~~*~~~ of the corresponding 1,2,3,6-tetrahydro compound. l-Ethoxycarbonyl- or 1,2diethoxycarbonyl- 1,2-dihydropyridazines were obtained similarly from alkali treatment of 1,2-diethoxycarbonylhexahydropyridazines.'38

c. TAUTOMERISM OF DIHYDROPYRIDAZINES Dihydropyridazines without substituents on the nitrogens exist as 1,4and/or 4,5-dihydro tautomers, often in equilibrium with one another. As mentioned in Section 111,D,2,it was found, for instance, that the ratio of 28a to 28b in deuteriochloroform is 1% In bromobenzene, the ratio is approximately 1:9.5. H. Lund and J. Simonet, C.R. Hebd. Seances Acad. Sci., Ser. C 277, 1387 (1973). G. Rosseels, Ing. Chim. (Brussels)46,7 (1964). ' 3 4 G. Rosseels, Ing. Chim. (Brussels) 42,285 (1960). l J s K. Alder, H. Niklas, R. Aumuller, and B. Olsen, Justus Liebigs Ann. Chem. 585,81 (1954). 136 L. J. Altman, M. F. Semmelhack, R. B. Hornby, and J. C. Vederas, Chem. Cornrnun.,686 (1968). 13' L. J. Altman, M. F. Semmelhack, R. B. Hornby, and J. C. Vederas, Org. Prep. Proced. Int. 7,35 133

(1975). lJ8

M. Rink, S. Mehta, and K. Grabowski, Arch. Pharm. (Weinheim, Ger.) 292,225 (1959).

40

ALEXANDER L. WEIS

[Sec. 1V.D

Crossland and Avellen' l o observed that addition of trifluoroacetic acid to a chloroform solution of 28a and 28b shifts the equilibrium entirely toward the 4,5-dihydro tautomer (28a).Neutralizing the solution, however, restores the original equilibrium. Equilibrium positions were also determined for two other 3,6-diaryl compounds, and in both cases the equilibrium favored the 1,4dihydro tautomer. The ratio of 4,4-dimethyl-3,6-diphenyl-1,4-dihydropyridazine (81) to the 4,5-dihydro tautomer is 3.4:1, the 3,5,6-triphenyl compound 35 is found solely in the 1,Cdihydro form, probably because of conjugation stabilization.

(81)

(82)

As expected, the position of equilibrium varies significantly with the substituents at the diene termini. 3,6-Di-tert-butyldihydropyridazine (82)shows 3.4:l for the ratio between the 4,5-dihydro tautomer to the 1,4dihydro species and, as was noted earlier, the 3,6-dimethoxy- and 3,6bis(dimethy1amino)dihydropyridazines exist completely in the 4,Sdihydro form. The difference in free energy, A G O , between the two tautomers can be calculated from the ratio of the two forms in solution using Eq. (23),in which K , = [4,5-dihydropyridazine]/ [1,4-dihydropyridazine]. A G O

= RTlnK,

(23)

In the case of the 3,6-diphenyldihydropyridazines28a and 28b,a value for of 1.24 kcal mol-' in deuteriochloroform is indicated. For the 3,6-di-tertbutyl tautomers, a value of only 0.73 kcal mol-' is obtained. A G O

D. PHYSICOCHEMICAL PROPERTIES 1. Infrared Spectra The correlation of dihydropyridazine structure with absorption maxima in the IR region has not been systematically studied. Information presented here has been gleaned from data contained in original works. Dihydropyridazines usually give characteristic bands in the following regions: 3200-3500 cm(vNH), 3000-3100 cm-' (vH-CXN, vH-C=,), 1400-1700 cm-' (vc=C, v,,,), and 700-950 cm-' (vH-C=C, vH--C=N). 48.74.8 1,82.88,89.95.10 1,102.107,126 All dihydropyridazines show absorption in the 1400-1700 cm-' region which is

'

Sec. IV.D]

DIHY DROAZINES

41

assigned to the C=C or C=N stretching modes. Two intense absorption bands have been reported for 1,4-dihydropyridazines at 1590- 1630and 16501670 cm-'. However, some discrepancy exists in the assignment of these bands. Some workers80.81*'26designate the former as the C=N stretching mode and the latter as the C=C stretching mode. Other authors95reverse the assignment. According to Zelenin et a1.,80*81 the first band falls in the region representing unconjugated hydrazones of ketones, while the second is common to enamines and enehydrazines. Interestingly, the reported stretching mode of the conjugated C=N-N= for 2,3-dihydroC for 4,5-dihydropyridazine (40a)95and C=C-C=N-N pyridazine (36)88fragments were below 1600 cm-'. The measured C=C stretching mode in the C=C-N=N fragment of 5,6-dihydropyrazine (79)is 1675 cm-1.48 All N-unsubstituted dihydropyridazines absorb in the 32003450 cm- ' region and show the characteristic stretching frequencies for ~ ~number ~ ~ ~and~ ~ ' ~ ' bonded and nonbonded N H g r o ~ p s . ~ ~ The position of these depend on structural factors and on the conditions of measurements. Absorption in this region has been used for structural

determination^.^^^^^ 2. Ultraviolet Spectra Only isolated UV spectra appear in the original literature. For the 5,6dihydro compound (79) in hexane, two absorption maxima have been reported, presumably the n + n* transition at 268 nm ( E 2100) and the n + .n* transition at 447 nm ( E 150).48 4,5-Dihydropyridazines (69) have one maximum at 285-287 nm,lZ1whereas 40a absorbs at 263 ( E 700) and 232 nm (E 1250).956-Methoxycarbonyl-4,4-dimethyl-1,4-dihydropyridazine (48)has two maxima,"' at 278 ( E 1600) and 247 nm ( E 4600), the long wavelength absorption normally being attributed to the n + II*transition. 2,CDiphenyl1,2-dihydropyridazine (37)89showed three absorption bands in methanol: at 232 (E 12300),274 (E 9500), and 370 nm ( E 220).

3. Nuclear Magnetic Resonance Spectra Nuclear magnetic resonance is an invaluable tool for investigating dihydroazines and, in particular, the dihydropyridazines. Unfortunately, until recently, most investigators have reported only proton resonance data. No doubt, in the future, more attention will be paid to I3C and 15N,which can contribute much information. The most useful applications of NMR have been in structural determinations and in identifying the presence of tautomeric equilibria. Table I summarizes some typical dihydropyridazine spectra. The chemical shifts of the ring protons at unsaturated centers range from 6 4.5-7.0. As might

TABLE I SELECTIVE 'H-NMR DATAOF DIHYDROPYRIDAZINES '3

64

6,

'6

Structure

(NH'

H3

H4

HS

H6

J3,,

1,2-Dihydro34b 38 1,4-Dihydro-

-

-

5.53 5.70-7.67

5.53 5.70-7.67

-

1.34

5.70-7.67

2.63 2.66 2.52 2.50 2.50 2.43 2.53 3.35 3.56 4.85 2.60

4.08 4.36 4.30 4.04 3.97 4.12 4.20 4.95

61

3Ob

-

-

31a 31b 31c 31d 31e 31f 28b 35 37a 37b 48

-

5.98 6.18 6.06 5.98

50a

5Ob 5oc 5od

5oe 51a

51b 51c

51d 57a

-

__ -

8.15 -

~

-

-

~

8.24 8.92 8.58 7.85 7.85 8.60 8.20 8.27 8.55 8.40

6.13

-

-

-

6.56

3.80

-

~

~

-

-

-

3.13

-

-

-

-

-

-

~

-

5.3 1 4.91 5.40 4.45 4.40 -

6.08 4.61 5.35 5.52 5.55 5.50 4.70

J4,s

J5,6

J4.6

Solvent

-

-

-

-

-

-

-

CCI, CDCI,

-

-

-

6.32 6.35

-

3.0 3.3 3.3 3.1 3.2 3.1 4.0 __ 6.0 5.3

-

-

-

6.00 5.95

-

-

-

-

-

6.93 6.13

-

-

-

-

-

-

-

-

6.31

-

-

-

--

-

-

-

6.34

-

-

-

6.9 6.7

-

-

-

-

7.5 7.5

-

2.5 7.5 7.5

-

8.0 ~

-

-

-

-

-

-

~

~

-

- -

6.7 7.0

-

6.25 6.38 6.10

Reference

-

-

CCI, CCI, CCI, CCI, CCI, CDCI, CDCI, CDCI, CDCI, CDCI, CCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI, CDCI,

-

-

-

86 89 81 83 83 83 83 83 83 22,87,100 22.87 88 88 101 102 102 102 102 102 102 102 102 102 107

-

4.50 4.62 4.73 4.83 4.91 4.75 4.91 4.90

6.72 6.04 6.06 4.73 4.83 7.01 6.98 6.98

6.75 5.94 5.72 5.64 5.48 5.77 6.35 6.33 5.60-5.90 5.74 5.82 5.85-6.35 5.80

5.99 6.10 6.22 6.02 5.94 5.90 5.94 5.48 6.14 5.98 5.88 5.92-6.41 6.18 6.38 5.85-6.35 5.60

4.25 3.42 4.43 6.52 3.35 3.17 3.32 3.10 3.41 3.75 4.40 4.21 4.3 1 4.28 -

-

2.71 2.02

-

5.2

58a 70a 70b

6.72

7oc

-

7od 73b 73c 7% 7% 1,6-Dihydro36a 36b 36c

46 56a 71a 71b 71e 71d 71e 71f 72a 72b 7M 724? 80 4,SDihydro28a 82 5,6-Dihydro79

3.10

-

-

-

-

-

6.34 6.20

-

6.95 6.66 -

6.70-6.95 -

5.70

-

-

3.05 2.78 3.18 2.78 2.65 2.81 3.02

-

-

7.7

1.1

-

-

-

10.0

1.2

CDCI, CDCI, CDCI, CDCI,

-

8.0 8.5

1.5 1.2 -

-

-

-

10.0

5.0 5.3 5.0 4.0

-

-

-

9.5 9.5

3.6 4.0

~

-

-

-

-

9.5 10.0 9.5 10.0 10.0 10.0

4.0 4.0 4.5 4.0 4.0 4.0

-

-

-

10.0

-

3.5

CDCI, CDCI, CDCI, CDCI,

-

2.0 -

0.9

CDCI, CDCI, CDC1, CDCI, CDCI, CDCI, CDC1, CDCI, CDCI, CDCI,

-

-

-

-

107 126 126 126 126 127 127 127 127 88 88 88 100 107 127 127 127 127 127

-

CDCI, CDC1, CDC1, CDCI, CDCI,

127 127 127 127 48

2.71 2.02

CDCI, CDCI,

22 22

1.60-2.00

CDCI,

48

-

-

1.5 1.5 -

44

[Sec. 1V.E

ALEXANDER L. WEIS

be expected, proximity of an electron-withdrawing substituent on a ring nitrogen results in shifts to lower fields. Ring protons at saturated centers produce signals at 6 2.4-3.2. Vicinal coupling constants across a double bond (CH=CH, J = 6-10 Hz) are generally larger than those across a single bond (=CHCH, J = 2-4 Hz). The NH protons have been found for 42dihydropyridazine at 6 1.34, whereas for 1,6-dihydro compounds at 6 5.7-6.3 and for the 1,Cdihydro compounds at 6 8.1-8.8. The ring methylene protons are usually equivalent, indicating, apparently, a rapidly occurring interconversion. Long-range coupling constants across the ring are frequently observed (see Table I).

E. REACTIVITY The chemical properties of dihydropyridazines were not studied systematically until now, and information about these compounds is almost completely absent. The only known property of most of the N-unsubstituted dihydropyridazines is that they can be easily oxidized (very often spontaneously in air) to the corresponding aromatic pyridazines. Padwa and Gehrlein reported'39 that excited-state behavior of 1,6dihydropyridazines differs from that of other diazacyclohexadienes. Thus photooxidation of 2,5,6-triphenyl-l,6-dihydropyridazine(36a) in 95% ethanol gave pyridazinone (83).However, when irradiation of dihydropyridazines (36) was carried out in cyclohexene in the presence of fumaronitrile, a [2 + 23 cycloadduct (84) was obtained. Furthermore, the authors noted that the dihydropyridazine system underwent a deep-seated skeletal rearrangement when treated with aqueous acid. Thus reaction of 36a with aqueous hydrochloric acid results in the formation of 1,3,4-triphenylpyrazole (85) [Eq. (24)].

(83)

(Ma)R = Ph (36b) R = Me

N' I

Ph (85)

' 39 A. Padwa and L. Gehrlein, J . Heterocycl. Chem. 12, 589 (1975).

Sec. V.B]

DIHYDROAZINES

45

As mentioned above, unsubstituted 4,Sdihydropyridazine and its simple derivatives readily dimerize or t r i m e r i ~ e . ~ ~ . ’ ~ ~ . ’ ~ ~

V. Dihydropyrimidines A. GENERAL COMMENTS Formally, five structures can be drawn in two dimensions for the isomeric dihydropyrimidines. However, most of the known dihydropyrimidines have either the 42- (9a) or the tautomeric 1,4- (9b) and 1,6- (9c)dihydro structures (Section 111,B). The chemistry of dihydropyrimidines is virtually a closed book owing to an absence of efficient synthetic methods. Moreover, there is also a dearth of quantitative data on the stabilization-destabilization effects of substituents on these ring systems. In addition, structures and relative stabilization of the various isomers and the tautomeric 1,6- and 1,4-dihydropyrimidines, in particular, were unknown until recently. In most published reports, suggested structures for products have been proposed with insufficient information to justify the given assignments. Early work on dihydropyrimidines is scattered throughout the exhaustive monographs of Brown on pyrimidine^.'^'.'^^ This survey, therefore, will aim to highlight the latest synthetic achievements in the preparation of dihydropyrimidines, along with unambiguous spectral assignments and confirmed tautomeric exchanges characteristic of these compounds.

B. SYNTHESIS 1. Cyclization Methods a. From a$-Unsaturated Carbonyls. The reaction of amidines with readily available a$-unsaturated carbonyl compounds is an attractive (3 + 3) approach to dihydropyrimidines. However, until recently, only a few reactions of this type were known, the result of a fortuitous combination of reaction conditions and starting materials. Traube and Schwarz prepared 140 14’

14’

P. De Mayo, J. B. Stothers, and M. C. Usselman, Can. J . Chem. 50,612 (1972). D. J. Brown, in “The Chemistry of Heterocyclic Compounds” (A. Weissberger, ed.). Wiley (Interscience), New York, 1962. D. J. Brown, in “The Chemistry of Heterocyclic Compounds” (A. Weissberger, ed.), Suppl. 1. Wiley, New York, 1970.

46

ALEXANDER L. WEIS

[Sec. V.B

dihydropyrimidine (19) by heating benzamidine with mesityl oxide, to which they assigned the 4,5-dihydro structure 1 9 ~ ' ~[Eq. ' (25)]. Silversmith has shown that the spectral data (IR and NMR) contradict the proposed structure, but are consistent with either of the tautomeric 1,4- and 1,6dihydropyrimidines. It has been demonstrated that the product obtained by Traube and Schwarz exists in the solid state as a 2-phenyl-4,6,6-trimethyl1,6-dihydropyrimidine (19b), whereas in solution a tautomeric equilibrium mixture of the 1,4 and 1,6 forms is observed. Me

Me Me

Me

Me

H,N Me

(194

(19~

In a second example, R ~ h e m a n n ' ~found ' that the reaction of benzamidine with benzilideneacetylacetone at 100°C results in the loss of an acetyl group with formation of 6-methyl-2,4-diphenyldihydropyrimidine(MDHP) (20) [see Eq. (3l)] . The reason for the lack of follow-up on this synthetic route may be attributed to literature reports of failures to isolate or even observe the expected dihydropyrimidines, particularly in the case of the simple a$ethylenic aldehyde^.'^^"^^ Dihydropyrimidine formation from a,fl-unsaturated carbonyl compounds and amidines occurs via nucleophilic attack by amidine at the activated double bond (Michael-type addition), followed by ring closure and dehydration (see Scheme 4). In the course of confirming this reaction scheme, the intermediacy of tetrahydropyrimidines and dihydropyrimidines was demonstrated. Further improvements that facilitated each step of this reaction (using molecular sieves, DMSO, and air) led to a new one-pot synthesis of

"'W. Traube and R. Schwarz, Ber. Dtsch. Chem. Ger. 32,3163 (1899). 144

E. F. Silversmith, J . Org. Chem. 27,4090 (1962).

'45

S.Ruhemann, J . Chem. SOC.83, 1371 (1903).

146

R. M. Dodson and J. K. Seyler, J . Org. Chem. 16,461 (1951).

Sec. V.B]

47

DIHY DROAZINES

R2

R2

R 1 = H, Me, Ph, N H , , NHCOCH,, OCH,, SCH, R Z , R3, R4 = H, Me, Ph

pyrimidines 147-150 [Eq. (26)]. Moreover, this understanding has led to selective preparation of cyclic adducts of benzamidine with chalcone and cinnamic aldehyde.' ' MDHP (20), identical to the samples obtained by R~hernann'~'and Heyes and Roberts,' 5 2 was easily prepared from benzalacetone and benzamidine in benzene with azeotropic removal of water. s3 However, attempts to synthesize other dihydropyrimidines, particularly those with fewer and smaller substituents, failed. Therefore, in the author's laboratory, a new strategy to prepare these compounds was proposed, which executes the two key steps in the reaction mechanism in separate stages: a preparation of hydroxytetrahydropyrimidine (86)[Eq. (27)], and dehydration of 86 to dihydropyrimidines (88). Usually a nearly quantitative yield of 6hydroxyl- 1,4,5,6-tetrahydropyrimidineswas achieved under mild conditions, and optimal methods of dehydration were developed. This gives a new and versatile synthetic route, enabling the preparation of a large variety of dihydropyrimidines (see Table 11). First step: R3

P3

(86) V. P. Mamaev and A. L. Weis, Khim. Geterotsikl. Soedin., 1555 (1975). A. L. Weis and V. P. Mamaev, Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 91 (1975) [CA 84, 121755t (1976)J 149 A. L. Weis, V. M. Shirina,and V. P. Mamaev,Izv. Sib. Otd. Akad. NaukSSSR, Ser. Khim. Nauk, 144 (1975) [ C A 84,105528r (1976)l. A. L. Weis and V. P. Mamaev, Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 147 (1975) [CA84,121763u (1976)l. A. L. Weis and V. P. Mamaev, Khim. Geterotsikl. Soedin., 674 (1977). T. D. Heyes and J. C. Roberts, J . Chem. SOC.,328 (1951). 153 A. L. Weis and V. P. Mamaev, Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 148 (1975) [ C A 84, 121764~(1976)l. 14'

14'

TABLE 11 PREPARATIONOF 6-HYDROXYTETRAHYDROPYRIMID1NE.S (86)AND

1,4(1,6)-DIHYDROPYRIMIDINES (88) 86

Substances

R2

a

H

H

h

H

H H

C

H

d

H

e

H

f

H

g

Me Me Me Me Me Me Me Me Me

h i

i

k I m 0

a

R’

H H H COMe COMe C0,Me C0,Et C0,Et C0,Et C02Et C0,Et C0,Me

R’ Ph Ph Ph H H H Ph Ph Ph Ph Ph p-N02C6H4 m-N02C6H4 o-NO~C~H~ o-NO~C~H~

The isolated yield of analytical sample is indicated. Yield in parentheses according to NMR. Unstable compounds. Isomeric mixture.

R4

Yield (72)”

Ph Me H Ph Me

98 96 88 96 87 84 98’ 70‘ 83’ 89‘ 79‘ 72’ 74d 71’ 68‘

H

Ph Me Me Ph Me Me Me Me Me

88

Melting point (’C)

140-141 162-163 119-120 156-158 -

137-138 188-189 182-184 217-219 168-170 214-215 207-208 148-149 152-153

Yield (%)”

96 94 96 87 30(80)b 0.5(27)b 82 76 67 18 73

Melting point (“C)

144-145 137-138 -c

131-132 -c -

83-84 104-105 135-137 106-108 147-149

-

68 69

-

182-184 2w202

Sec. V.B]

49

DIHY DROAZINES

Second step:

P'

P'

Armed with these encouraging results, we attempted the preparation of the parent compounds in this series, a goal long sought by synthetic chemists. In the past, attempts to synthesize unsaturated dihydropyrimidines from the parent a,p-unsaturated carbonyl compound acrolein failed,'43*'46p'54*15 5 probably because of fast polymerization of acrolein in the presence of strong bases. Therefore, if one could interfere with this polymerization, the Michaeltype addition, leading to the desired product, could then proceed unhindered. Hydroquinone was found to provide the best such protection against polymerization of acrolein.' 56 By this method, 6-hydroxytetrahydropyrimidines(86) were prepared in high yield by dropwise addition of a solution of acrolein to a stirred solution of corresponding amidines in acetone at - 5°C under an inert atmosphere. Dehydration of these products was carried out by boiling in dimethoxyethane (or other solvents such as acetonitrile and DMF), giving 2-phenyl- and 2methyldihydropyrimidine in reasonable yields (Table 11). Unsubstituted dihydropyrimidine was also prepared by this method; however, high instability did not allow isolation in a pure state, and therefore only spectral verification could be provided. Good yields were also obtained by dehydration, using acid catalysis or acetic acid as a solvent. All dihydropyrimidines synthesized by this method exist in solution in tautomeric equilibrium of 1,4- and 1,6-dihydro compounds (Section V,C,l). Besides the high yields of dihydropyrimidines, another valuable advantage of this method is that one can usually follow the transformation to dihydropyrimidine visually by choosing a suitable solvent, namely, one with a low solubility for hydroxytetrahydropyrimidine(86). Moreover, the reaction is very clean, and evaporation of the solvent alone usually gives an analytically pure dihydropyrimidinic product.

'55

A. Le Berre and C. Renault, Bull. Soc. Chim. Fr., 3146 (1969). A. L. Weis, Candidate's Thesis, Institute of Organic Chemistry,Siberian Division of tile USSR Academy of Sciences, Novosibirsk, 1975. A. L. Weis, F. Frolow, D. Zamir, and M. Bernstein, Heterocycles 22, 657 (1984).

50

[Sec. V.B

ALEXANDER L. WEIS

The initial product of dehydration of hydroxytetrahydropyrimidine 86 is the unstable 4,5-dihydropyrimidine 87, which presumably undergoes either thermal suprafacial [ 1,5]-hydrogen migration to the corresponding 1,6-

60.

Hog.ph‘ CH

HC<

,c=o

HO R

+

HN

\C-Ph

Jt.

H,N’

R

R

H

(89)

NP’h H (90)

Sec. V.B]

51

DIHYDROAZINES

dihydropyrimidine 88b or imine-enamine tautomerism to the 1,Cdihydropyrimidine 88a. Apparently, the rate of hydrogen migration is fast, since 4,5-dihydropyrimidines were neither isolated nor detected spectroscopically. However, some indirect proofs for intermediacy of 4,5-dihydropyrimidines were obtained. For example, in the reaction of o-hydroxyphenyl-a$-unsaturated carbonyl compounds 89 with benzamidine, instead of the desired dihydropyrimidine (90) (which is stabilized by intramolecular hydrogen bonding), the corresponding bridgehead compounds 92 were isolated. The key step in this reaction is likely the formation of highly reactive 4,5-dihydropyrimidine 91, which is rapidly attacked by the phenolic hydroxy group before it undergoes proton migration to the stable dihydropyrimidine [Eq. (29)].15’ Moreover, in the course of structural investigations, the deuterated dihydropyrimidine was prepared for specific assignments of protons at C-4 and C-5 by the sequence given in Eq. (30). 0 PhCHO+CD,CCD, II

- { HNyph +

D

-0

H,N

CD3 Ph

Ph

66%

34%

The ratio of deuteration at position 5 clearly indicates a kinetic isotope effect during the transformation of 4,s-dihydropyrimidine to the more stable tautomeric 1,4- and 1,6-dihydro compounds. The mechanism of this hydrogen migration needs further study. It would be interesting to compare the rates of and substituent influences on this migration with the similar processes in the last step of Hantzsch’s synthesis of dihydropyridines (Scheme 3) and in hydrogen migration in the dihydropyridazine series (Section IV,C). A reinvestigation of Ruhemann’s reaction has clearly shown that-in conformity with the proposed mechanism-the initial product formed is hydroxytetrahydropyrimidine (86g),which, depending on reaction conditions, may be transformed to 5-acetyldihydropyrimidine (88g) [Eq. (3 l)].

’” A. L. Weis, F. Frolow, M. Bernstein, and J. Fahima, Isr. Chem. SOC.,49th Annu. Meet., 1982, p. 55 (1982); J . Org. Chem. 49,3635 (1984).

52

[Sec. V.B

ALEXANDER L. WEIS Ph

\ + HzN>Ph HN '

PhCH{' -0

Ph

Me'

Me H (8%)

The loss of the acetyl group in ethanol may be explained in terms of solvent participation under base catalysis.

cH3H:c1ph Ph

I1

Me

H

Ph

Me

Ph

H

H-OC,H,

(8W

(20s)

However, in the case of benzylideneacetoacetic esters, which have two distinct carbonyl groups and, therefore, two different possibilities for ring closure, the more reactive ester group usually participates in the pyrimidine ring formation. By using the reaction pathway developed in our laboratory, reaction of the ester function can be avoided, and high yields of dihydropyrimidines are obtained from hydroxytetrahydropyrimidines. This is an attractive route for preparation of 5-functionalized dihydropyrimidines,'58

"*

A. L. Weis, Israel Patent Application pending. A. L. Weis and R. Vishkautsau, lsr. J . Chem. (1985) (in press).

Sec. V.B]

53

DIHY DROAZINES

which are physiologically active compounds with interesting antioxidant and membranotropic properties, as well as low toxicity, and which are also analogues of the calcium antagonist nifedipine (see Section I). 3 R J - - + ~ e M II 0

,COOR2 + HzNtR3<

H

R’CH=C, ,C=O

HN R200C

Me

R20::$lR3 Me

Me $ 1 R 3H

H

86(i-o)

tN(i-0)

b. From 8-Dicarbonyl Compounds. The four-component condensation reaction of 8-dicarbonyl compounds with ammonia (or ammonium salts) and carbonyl-containing substances is a convenient and rather promising (3 + 1 + (1) + 1)-fragment approach for the preparation of 1,2-dihydropyrimidines(Scheme 6).

+ o=c\/

-[fJ]

-fJ H

SCHEME 6

Formally, one can also propose the formation of the 2,5-dihydro isomer, but even if this isomer does form during the reaction, it is easily transformed to the thermodynamically more stable 1,Zdihydro compound. This reaction is nearly identical to the classical Hantzsch’s synthesis of dihydropyridines, with only the molar ratio of starting materials being changed. However, in contrast to the widely investigated Hantzsch reaction, there are few examples in the literature, and it needs detailed study. This original approach was first used in 1964 by Krohnke and coworkers’ 5 9 for preparing dihydropyrimidines, but these spontaneously decomposed to the corresponding pyrimidines and could not be isolated.

’” F. Krohnke, E. Schmidt, and W. Zacher, Chem. Ber. 97, 1163 (1964).

54

[Sec. V.B

ALEXANDER L. WEIS

Hoffmann and c o - w o r k e r ~first ~ ~ successfully ~'~~ isolated 1,2-dihydropyrimidines 93 from a condensation of the dimethylacetal of acetoacetic aldehyde with different carbonyl-containing compounds in the presence of ammonia and ammonium nitrate [Eq. (32)].

Usually, these compounds are rather unstable at room temperature, although they could be stored in a freezer. Several authors have used this method for the preparation of 1,2-dihydropyrimidine~.'~'-'~~ However, the majority of the compounds isolated were disubstituted in position 2, preventing further oxidation to corresponding pyrimidines. Salts of 1,2-dihydropyrimidines 95 were also prepared by a clever modification of this approach, which instead of a mixture of ammonia and carbonyl derivative, used a gem diamine (94) in condensation with acetylacetone or pmethoxyacrolein under acidic condition^'^^ [Eq. (33)].

H

(94)

(95n:R = Me, X = CIO,) (95b:R = H, X = CI)

c . Other Cyclizations. Barluenga et al. have shown ,that N-substituted 1,2-dihydropyrimidines 96 are obtained with high yields in an aluminum chloride-catalyzed reaction of diimines, carbonyl compounds, or their acetals' 65* CEq. (341.

'

S. Hoflmann and W. Shultze, Patent, DDR 48617 (1966)[CA 66,28793(1967)l. D. Lloyd and H. McNab, J.C.S. Perkin I, 1784 (1976). H.-J. Teuber, G . Schutz, and W. Kern, Chem. Ber. 108, 383 (1975). 1 6 3 A. L. Weis and V. Rosenbach, Tetrahedron Lett., 1453 (1981). G . A. Reynolds, G. H. Hawks, and K.H. Drexhage, J. Org. Chem. 41,2783(1976). 16' V. G. Aranda, J. Barluenga, V. Gotor, and S. Fustero, Synthesis, 720 (1974). 166 J. Barluenga, M. Tomas, S. Fustero, and V. Gotor, Synthesis, 346 (1979). 161

Sec. V.B]

55

DIHY DROAZINES

+x=c'

R4 'H

X

=

-

R'dl*4

(34)

Ph

H

i

R'

NH.0

(96)

Recently, it was reported that imidoylketene imines (97) rearrange at room temperature to form corresponding N-substituted 1,2-dihydropyrimidines 98 via a [1,5]-hydrogen shift16' [Eq. (35)]. Me

R3

(9)

(98)

Takamisawa and co-workers described an unusual cyclization with formation of the ethyl ester of 2-methyl-l,6-dihydropyrimidine-5-carboxylic acid (99), observed by interaction of 2-ethoxymethoxymethyI-3-ethoxypropionitrile with acetamidine16* [Eq. (36)]. EtOCH'CHCN

1

CH MeO"0Et

+"'">Me HN /

HCI EtOH

EtOOC

(99)

In Poland, Kuran and co-workers demonstrated the formation of dihydropyrimidines by reaction of methyl aluminates with acrylonitriles.'69*170

2. From Pyrimidine Derivatives a. Addition of Organometallic Reagents. Several reactions of organolithium compounds or Grignard reagents with pyrimidine and derivatives have been reported to give a mixture of 2- and 4-substituted J. Goerdeler, C. Lindner, and F. Zander, Chem. Ber. 114,536 (1981). A. Takamisawa, S. Hayashi, and K. Tori, Yakugaku Zasshi 78,1166 (1958). W. Kuran and S. Posynkiewicz, J . Organomet. Chem. 23,343 (1970). ' l oW. Kuran, Pr. Nauk, Politech. Warn.,Chem. 7 , 72 (1972).

56

ALEXANDER L. WEIS

[Sec. V.B

52.1 7 1-1 73 (via spontaneous or KMnO, oxidation of the corresponding unstable dihydropyrimidines). Most of these early reactions were aimed at preparing the substituted pyrimidines, and the dihydropyrimidine intermediates were never isolated and seldom identified. Heyes and Roberts’52 described the first preparation of a compound formulated as 1,6dihydro-4-methyl-2,6-diphenylpyrimidine (20b) by reaction of 4-methyl-2phenylpyrimidine with phenyllithium.

It has been shown that this compound in the solid state has the 1,4dihydropyrimidine structure 20a,24 whereas in solution it exists in a tauto” (see Section V,C,l).Unpublished meric equilibrium of 20a and 20b23*249’ data on the preparation of 1,6-dihydropyrimidine by treatment of pyrimidine with tert-butyllithium was mentioned earlier.”4 However, the action of

R = Ph, 2-thienyL 3-thienyl,2-furyl, I-methyl-2-pyrroly1,3-pyridyl H. Bredereck, R. Gompper, and H. Herlinger, Angew. Chem. 70, 571 (1958). H. Bredereck, R. Gompper, and H. Herlinger, Chem. Ber. 91,2832 (1958). S. Gronowitz and J. Roe, Acta Chem. Scand. 19, 1471 (1965). 174 R. F. Evans, unpublished results, from Brown.I4’

17’ 17’

Sec. V.B]

57

DIHY DROAZINES

organolithium reagents (particularly,aryl- and hetaryllithiums)on pyrimidine and derivatives has been developed more recently by van der Plas et al. as a 76 useful synthetic method for the preparation of dihydropyrirnidine~.’~~*~~’*~ This reaction usually occurs at unsubstituted positions. Thus in the case of pyrimidines, a mixture of 1,6- (or 1,4-)(100)and 1,2-dihydropyrimidines(101) is formed [Eq. (37)]. However, the formation of 1,6- or lP-dihydropyrimidines predominates. On the other hand, when only one unsubstituted or sterically less hindered position is available, a single product results, as in the case of 5-cyano-4,6-dimethoxy-2-ethyl-2-methyl1,2-dihydropyrimidines (102).177

Ncp OMe

EtMgBr

Me0

I

OMe

M“e 0t L M eEt

N M ’e

H (102)

Another interesting example of this type of reaction is the nucleophilic addition of butyllithium to 4,6-dialkoxypyrimidines to give the 2-butyl-4,6dialkoxy-2,5-dihydropyrimidine(104), probably via the intermediate 42dihydropyrimidine 103178[Eq. (38)]. A series of dihydropyrimidines of this type was prepared analogously in the author’s lab~ratory.’~’ OR

OR

b -RotL:u-

RO

Li

PR a. R = M e b. R = Et C. R = BU

H

R. E. van der Stoel and H. C. van der Plas, J.C.S. Perkin I, 1288 (1979). R. E. van der Stoel and H. C. van der Plas, J.C.S. Perkin I, 2393 (1979). 1 7 7 H. Yamanaka, K. Edo, and S. Konno, Yakugaku Zasshi 97,726 (1977). M. D. Mehta, D. Miller, and E. F. Mooney, J. Chem. SOC.,6695 (1965). A. L. Weis and G . Kaminas, unpublished results (1983).

175

PR

58

[Sec. V.B

ALEXANDER L. WElS

The dihydropyrimidines 104 are the only known isolated compounds with 2,5-dihydro structures that can undergo oxidation to the corresponding pyrimidines. The existence of this structure may probably be explained by stabilization by the two alkoxy groups in positions 4 and 6.

b. Reduction with Complex Metal Hydrides. Despite the fact that a large number of dihydropyridine derivatives have been prepared by reduction of the corresponding pyridines or pyridinium salts with complex metal hydrides, no systematic investigation of this synthetic approach, with regard to the dihydropyrimidines, has been carried out. May and Sykeslso reduced a number of ethyl pyrimidine-5-carboxylates and 5-cyano- and 5-carbamoylpyrimidines with lithium aluminum hydride and obtained dihydropyrimidines of unknown configurations. The influence of groups occupying the 2-, 4-,5-, and 6-positions upon reduction with complex hydrides is unclear, although an electron-withdrawing moiety (C02Et,CN, etc.) in the 5-position appears to facilitate ring reduction. When ethyl 4-methyl-2-methylthiopyrimidine-5-carboxylate or ethyl 2,4dimethylpyrimidine-5-carboxylatewas treated with lithium aluminum hydride at - 70"C, preferential reduction of the ester group occurred, yielding the 5-hydroxymethyl derivative rather than ring reduction."' Shadbolt and Ulbricht reportedia2 reduction of a number of 2-methylthiopyrimidines by LiAlH, in tetrahydrofuran and by NaBH, in ethanol to form the corresponding 1,6-dihydro derivatives (105) [Eq. (39)].

-

EtOOC

EtOOC

R ,

t'SMe

(39)

H R

= CH=NOH,

CN. CI

(105)

Mamaev and Gracheva ~uggested"~that a yellow by-product, which was isolated from the reduction of 4,6-diphenylpyrimidin-2-one, is 1,2-dihydropyrimidine 2la. Although attempts to prepare an analytically pure sample of this material failed. Reinvestigation and consequent optimization of this reaction enabled the preparation of 21a in 78% yield.la4 The material was stable, could C. D. May and P. Sykes, J. Chem. SOC. C, 649 (1966). R. S. Shadbolt and T. L. V. Ulbricht, J. Chem. SOC.C , 733 (1968). IH2 R. S. Shadbolt and T. L. V. Ulbricht, J . Chem. SOC. C , 1203 (1968). I a 3 V. P. Mamaev and E. A. Gracheva, Khim. Ceterotsikl. Soedin., 596 (1968). I H 4A. L. Weis and R. Vishkaucan, Chem. Lett., 1773 (1984). la0

Sec. V.B]

59

DIHYDROAZINES

be purified, and provided single crystals for X-ray d i f f r a ~ t i o n In . ~ ~addition, NMR investigation has shown that enamine-imine tautomerism is present in CDCl, (Section V,C,2).

(214

(2W

The mechanism of this LiAlH, reduction of pyrimidine-2-ones should be similar to that of amides (Scheme 7). Therefore, we supposed that one should also be able to obtain 1,2-dihydropyrimidine (21a) by reduction of the corresponding 4,6-diphenylpyrimidine (106), and, indeed, LiAlH, reduction of 106 in tetrahydrofuran gives 30-70% (depending on conditions) transformation of 106 to 21a. The reaction is very clean and only unchanged 106 was isolated. The reason for incomplete transformation of 106 is still unclear.'84

1 ,--. LiAIH4

,,--.,

'

H20

"N H

AIH,Li'

SCHEME I

This reaction was extended to other derivatives. Thus 2-phenyl-1,6dihydropyrimidine was prepared by LiAlH, reduction of 2-phenylpyrimidin4-one or 2-phenylpyrimidine. Undoubtedly, there is great potential in the reduction of pyrimidines with complex hydrides, and this approach should attract wide attention in the future.

c. From 4-Halopyrimidines. 1,6-Dihydropyrimidines 107 were isolated as a side-product in the zinc-acetic acid-catalyzed ring contraction of

60

[Sec. V.B

ALEXANDER L. WEIS

pyrimidines to pyrroles. Thompson and ~ o - w o r k e r sdemonstrated ~ ~ ~ * ~ ~ ~that dechlorination is the initial step in reductive dehalogenation of 4-dichloropyrimidines with zinc in 50% aqueous acetic acid. According to the mechanism they proposed, further reductive attack of zinc occurs at the 1,6 site of the pyrimidine ring, as shown in Eq. (41).

a: R = Ph, R’ = Me b: R = Me, R’ = p-ClC,H, c: R = Me, R‘ = CH,COOEt

d. Electrophilic Aromatic Substitution with Protonated Pyrimidines. Girke18’ showed that, in the presence of trifluoroacetic acid, pyrimidine and 5-methylpyrimidine react with a number of active aromatic compounds to form stable 4-aryl-substituted dihydropyrimidium salts (108). Further, from these salts the dihydropyrimide bases 109a and/or 109b can be obtained. The mechanism for this attractive and novel reaction is apparently best described as an aromatic, electrophilic substitution by the protonated pyrimidine derivative at the electron-rich position of the active aromatic compound * [Eq. (42)].

R=H,Me

e. Desulfurization of Pyrimidine-2(1H)-thiones. Kashima et u1.’88*189 reported an independent preparation of three types of N-substituted 1,2-

’” T. W. Thompson, Chem. Commun., 532 (1968). J. L. Longridge and T. W. Thompson, J . Chem. SOC.C, 1658 (1970). W. Girke, Chem. Ber. 112, 1 (1979). L88 C. Kashima, M. Shimizu,A. Katoh, and Y. Omote, Tetrahedron Lett., 209 (1983); J.C.S. Perkin I, 1799 (1983). C. Kashima, unpublished results (1983).

Sec. V.B]

61

DlHY DROAZINES

(110), 1,4- (111), and 1,6- (112) dihydropyrimidines by the desulfurization of pyrimidine-2( 1H)-thiones and their dihydro derivatives with Raney nickel catalyst [Eq. (43)].

R3rNH +R3cx fiN R3G R 3 2 J ' R2

'

f N

R'

R4

-

R2

R2

R4M

NAS

I

R'

'NAS

I

R4

R'

I

R'

(43)

R3

N'I

R'

R' I

R4

I

R'

R4M = R4MgI, R'Li, NaBH,, or LiAIH4

Preparation of three different types of N-substituted stable dihydropyrimidines allows for an excellent comparative study of the spectral properties of these compounds, enabling unambiguous structural determinations of less stable congeners.

f. Electrochemical Reduction. Pyrimidine and some of its derivatives have been investigated by classical and ac polarography, as well as by cyclic voltammetry. 190-19s Usually, pyrimidine gives rise to two one-electron waves in the acid region. These waves merge, in slightly alkaline solution, into a single two-electron wave, followed by a second two-electron wave, which results in the formation of a tetrahydropyrimidine. The structures of most of the electrochemical reduction products have been deduced from their UV spectra.

lg5

D. L. Smith and P. J. Elving, J . Am. Chem. SOC.84,2741 (1962). D. L. Smith and P. J. Elving, Anal. Chem. 34,930 (1962). J. E. OReilly and P. J. Elving, Electroanal. Chem. 21, 169 (1969). P. J. Elving, S. J. Pase, and J. E. OReilly, J . Am. Chem. SOC.95,647 (1973). D. J. Trenevot, Electroanal. Chem. 46,89 (1973). P. Martigny and H. Lund, Acta Chem. Scand. Ser. B B33,575 (1979).

62

[Sec. V.B

ALEXANDER L. WEIS

Interesting results by Martigny and L ~ n dhave ' ~ shown ~ that 2-phenylpyrimidines (113) are reduced in a four-electron reaction with ring contraction to 2phenylpyrroles [Eq. (44)]. The site of reduction depends significantly on the ring substituents. Thus, for instance, the presence of a phenyl group at position 2 of the pyrimidine ring changes the usually observed 1,6- to a 1,2-reduction. The latter was proved by the observation that if the reduction of 113 in DMF is halted after the consumption of two electrons, hydrolysis of the product gives benzaldehyde.

tlph aMIh 2e-

Me

+ 2H+,

252%

Me

(44)

Me

H

H

3. Miscellaneous Polychlorinated 2,5-dihydropyrimidine 114 was obtained by reaction of phosphorus pentachloride with $5-diethylbarbituric acid. Further treatment with zinc in neutral aqueous solution gave 2,5-dihydropyrimidine 115 dehalogenated at position 2'97*'98CEq. (491. 0

- yJcl -;el6 CI

CI

CI

0J f~ 0

(45)

H (114)

(115)

When a methanolic solution of 2,6,8-triphenyl-1,5-diazabicyclo[5.l.O]octa3,5-diene (116) was treated with sodium methoxide in methanol, a nearquantitative yield of trans-2-styryl-4,6-diphenyl1,2-dihydropyrimidine (117) was obtained.'99 Among the products formed by the 1,3-dipolar cycloaddition reaction of benzonitrile-p-nitrobenzylideto 3-phenyl-2H-azirines (in benzene under basic '91

lg7 19' '91

A. W. Dox, J . Am. Chem. SOC.53, 1559 (1931). A. W. Dox, J . Am. Chem. SOC.53,2741 (1931). K. Folkers and T. B. Johnson, J . Am. Chem. SOC.55,2886 (1933) A. Padwa and L. Gehrlein,J . Am. Chem. SOC.94,4933 (1972).

Sec. V.C]

63

DIHY DROAZINES

(117)

(116)

conditions), 24 p-nitrophenyl)-4,5,6-triphenyl-1,6-dihydropyrimidine (1 18) was isolated'" [Eq. (47)].

C6H4N02

(118:R = Ph)

An attractive method for the preparation of 1,2-dihydropyrimidines119 by rearrangement of 1 -benzyl-3,5-dimethylpyrazolein the presence of sodium amide has been reported201[Eq. (48)]. Me

.Me

I

CHRPh

I

Me

H

R = H, Ph

c. TAUTOMERISM OF DIHYDROPYRIMIDINES 1. Tautomerism of 1,4- and 1,4-Dihydropyrimidines a. Structures of the Tautomers. Any fruitful discussion of tautomeric equilibria must be predicated upon a firm knowledge of the structures of the 2oo '01

N. S. Narashimhan, H. Heimgartner, H.-J. Hansen, and H. Schmidt, Helu. Chim. Acta 56,1351 (1973). B. A. Tertov and Yu. G . Bogachev, Khim. Geterotsikl. Soedin., 119 (1981).

64

[Sec. V.C

ALEXANDER L. WEIS

isomers involved. However, the structures and relative stabilities of the tautomeric 1,4- and 1,6-dihydropyrimidines have been unresolved until recently. The available literature on the structure of 1,6- and lP-dihydropyrimidines has been quite speculative. Particular assignments for both forms have been proposed with insufficient information to justify the suggested preference. The majority of publications describe products as being in one of their possible tautomeric forms, usually the 1,6 form (B), without relating at all to the possibility of a tautomeric m i ~ t ~ rOthers e suggest . ~ either a completely delocalized structure X2O0or a time average of rapidly without assignments for the interchanging tautomers A and individual isomers. B,'44*'74,'759'87

c" IN)-/

CJH-Cj""

H

-N.

N

X

B 14

A 1,4

In 1975, Weis and Marnaevls3 showed that the 6-methyl-2,4-diphenyl dihydropyrimidine (MDHP) (20), which was obtained by condensation of benzylidene, acetone, and benzamidine, exists in solution in a tautomeric equilibrium of 6-methyl-2,4-diphenyl- 1,4-dihydropyrimidine (20a)and 6-methyl-2,4-diphenyI-3,4-dihydropyrimidine (20b)[although the systematic nomenclature for structure 20b would be 4-methyl-2,6-dipheny1-1,6-dihydropyrimidine (see Section III,B), we have retained the original nomenclature to provide a convenient comparison of the two tautomers]. This tautomerism was detected by spectral studies (NMR, IR, and UV) of solutions of 20.Thus the NMR spectra of the two individual tautomeric structures can be observed in dipolar aprotic solvents such as dimethyl sulfoxide (DMSO) and hexamethylphosphoramide (HMPA).'53 Ph I

Ph I

ton

20b

(1,CMDHP)

(1,bMDHP)

However, when the IR and UV spectra of 20 were recorded, using solid samples (KBr), only one tautomer was present, but the final assignment of its

~

~

Sec. V.C]

DIHYDROAZINES

65

structure could not be made using these data alone. X-Ray diffraction, however, showed that in the crystalline state compound 20 exists in the 1,4dihydro form 20a.24 The combined X-ray, NMR, IR, and UV data enabled definite spectroscopic assignments for each of the tautomers of compound 20.Thus the IR v,,, band at 1700 cm-' was attributed to the stretching mode of the C=CNH-C=N fragment of 20a,whereas the new band at 1645 cm-', which appears in solution, is due to the C=C-N=C-NH fragment of 20b.The relative intensities of these absorption maxima, which depend on solvent polarity, give a qualitative estimate of the relative concentrations of each tautomer in a given solvent. Usefulness of IR and NMR data in assigning tautomer structure was further validated by structural elucidation of dihydropyrimidine 19 based on Silversmith's data.'44 Its structure was assigned as the 1,dtautomer 19b,based on a reinvestigation of its IR band at 1652 cm-', similar to the IR spectra of 20b.This was later confirmed by X-ray analysis.23 The infrared spectra of a series of these compounds were of particular interest. They showed a minimum of three important absorption bands at 1600-1700 ( V C ~ N ) , and 3200-3500 (vNPH) cm-'. HOW1550-1620 (v,,,), ever, characteristic absorptions in the 1600-1700 cm-' region provided an excellent tool for differentiation between the tautomers. It has been consistently observed in a large number of newly prepared compounds that the band assigned to the C=C-NH-C=N fragment of the 1,4 tautomers appears 30-60 cm-' higher in frequency than the corresponding band for the C=CN=C-NH fragment of the 1,6 tautomer. Intensity of these peaks correlates well with the ratio of tautomers in solution.

b. External Parameters Aflecting the Rate of Tautomerism. van der Plas et a1.174*175and Girke'*' have also studied the behavior of a variety of dihydropyrimidines, but attempts to obtain the NMR spectra in deuteriochloroform of each of the tautomers failed, even at - 88°C. Experiments in our laboratory confirmed this, demonstrating that in CDCl, solutions only the averaged spectra could be seen. This observation stimulated further investigations directed toward identifying the factors, enabling observation of annular tautomerism in dihydropyrimidine systems. The easily available and reasonably stable MDHP (20a) proved to be a convenient model for carrying out these measurements. In the course of NMR studies on 20 in DMSOd, solution, tautomerism was affected by the following factors: 1. Dryness of solvent. This was confirmed by the addition of small amounts of water to a sample in which slow exchange was observed. This causes an increase in the rate of proton exchange as indicated by the broadening of the

66

ALEXANDER L. WEIS

[Sec. V.C

H-4 and H-5 signals of both tautomers and a decrease in the separation between them. 2. Microconcentrations of H + ions in solution. The rate of exchange is greatly accelerated by the addition of catalytic amounts of H’; in each case, an “average” spectrum was obtained. 3. Paramagnetic impurities in solution also accelerate the rate of exchange. 4. Concentration dependence. It has been shown that the observation of the tautomers by ‘H NMR is only possible at 0.001-0.003 M concentrations. Thus this factor plays an extremely crucial role in our ability to detect tautomerism. Knowing that proton transfer between two heteroatoms is usually rapid (on the NMR time it may be expected that by using an aprotic dipolar solvent (DMSO, HMPA), a decrease in the rate of tautomerism should occur because of strong intermolecular hydrogen bonding with the solvent, enabling observation of the individual tautomers. The fact that in CDCI, only average spectra were observed may be attributed both to a lack of hydrogen-bonding stabilization and to minute amounts of acid which are usually present in this solvent. However, when the spectra were determined at low temperature (- 50°C) on a dilute sample (0.001 M) in CDCI, (initially filtered through alumina in order to remove traces of acid and degassed with argon), tautomerism is observed.202 Further, based on the above-mentioned encouraging results, a quantitative analysis of the kinetics of the tautomeric equilibrium is possible, and the external parameters that influence the rate of reaction can be c. Description of N M R Spectra. In Fig. 1, two ‘H-NMR spectra of MDHP in CDCI, are shown. The lower spectrum, at -6O”C, corresponds to the slow-exchange limit where signals due to the tautomeric forms 20a and 20b are completely separated. The upper spectrum in this figure was taken at room temperature and in a commercial, deuterated solvent. Here, the rate of tautomerism is fast and the observed peaks are at the weighted average positions of the corresponding tautomers. The NH peak in this spectrum, however, was not observed, owing to exchange with an impurity whose signal is strongly shifted from that of the NH. At -60°C (and in specially purified CDCI,), the positions of the NH signal were somewhat concentration dependent, and when water was present, so was the H 2 0 peak (see Fig. 1, A. L. Weis, Tetrahedron Lett., 499 (1982). A. L. Weis and Z . Porat, Isr. Chem. Soc., 49th Annu. Meet.. 1982, p. 46 (1982). 204 A. L. Weis, Z. Porat, and Z . Luz, J . Am. Chem. SOC.106,8021 (1984).

’O’

’03

Sec. V.C]

67

DIHYDROAZINES C

-1

' R

I

I

4

2

p' FIG.1 . 'H-NMR spectra at 270 MHz of a 0.026 M solution of MDHP in CDCI,. The lower and upper spectra were taken at -60°C and room temperature, respectively. The solvent used for the low-temperature measurement was purified by method d while for the room-temperature spectrum untreated commercial CDCI, solvent was utilized.

lower). All these peaks shifted to low field with increasing MDHP concentration, apparently owing to the formation of hydrogen-bonded complexes involving these molecules. MDHP spectra in DMSO at room temperature are shown in Fig. 2. The lower spectrum corresponds to a purified solvent, while the upper one corresponds to a regular commercial grade. As before, the two spectra correspond, respectively, to the slow and fast limits of proton exchange. Between this spectrum and the one in CDCl,, there is a large low-field shift of the NH peaks, apparently because of strong hydrogen bonding with the solvent. Also, the equilibrium constant K = [20b]/[20a] has decreased to 0.67, as compared with 1.27 in CDCl, .Two other minor differences are (a) that splitting of the H-4 signals is observed in DMSO but not in CDCl,, and (b) that the two methyl signals are degenerate in DMSO but not in CDC1,. Thus solvent polarity seems to affect chemical shifts of the protons, in particular the NH, as well as the equilibrium distribution of the two isomeric species.

68

[Sec. V.C

ALEXANDER L. WEIS

H-4

H -5

H20

A I

I

8

8

I

I

6

6

4

6

2

s4 (pprn)

FIG.2. 'H-NMR spectra(270 MHz) of a 0.04 M solution of MDHP in DMSO-d,. The spectra were taken at room temperature using a purified (lower) and untreated (upper) solvent.

TABLE 111 CHEMICAL SHIFTS OF THE NH PROTONS AND EQUILIBRIUM CONSTANTS FOR MDHP IN SEVERAL ORGANIC SOLVENTS TAUTOMERISM Temperature ("C)

Concentration

Solvent CDCI, CDCI, CDCI, Dioxane-d, DMSO-I, HMPA-d,,

- 60 - 60 - 60 15 25 25

0.013 0.073 0.121 0.0 1 0.01 0.01

(W

NH(A) ( P P ~ 6.18 6.30 6.54 7.19 8.56 9.35

NH(B) (PP~) 5.56 5.74 6.08 6.75 8.05 8.90

K

=

CBI/CAI

1.27 1.27 1.27 0.82 0.67 0.50

In Table 111, chemical shift data for the NH peak and equilibrium constants in four solvents are summarized, and the results are arranged according to increasing solvent polarity: CDCI, < dioxane < DMSO < HMPA. There is a significant low-field shift of the NH resonance of both tautomers with increasing polarity, apparently owing to formation of hydrogen-bonding

Sec. V.C]

69

DIHYDROAZINES

complexes with the solvent. In CDCI,, there is also a low-field shift of the N H signal with increasing MDHP concentration, indicating the formation of dimers or higher clusters. This concentration effect on the N H shift exists only in CDCI, and is essentially absent in the other solvents studied. The equilibrium distribution [20b]/[20a] also decreases monotonically with increasing polarity, suggesting that in MDHP form A is more polar than form B. In general, the tautomeric transformation between the two forms A and B is slower in the more polar solvents. Thus separate signals for the two tautomers can readily be observed even in unpurified HMPA, whereas in CDCI, it can be seen only in purified solvent and very dilute solutions. The proton-transfer process is hindered by the formation of the hydrogen-bonded complexes with the polar solvents. Finally, l3C-NMR spectra in CDCI, (at -60°C) and DMSO, both corresponding to the slow-exchange limit, are shown in Fig. 3. Rationalization of these spectra is similar to that discussed above for the 'H-NMR results. Ph

Ph

H

a

(20A) C-2

/ \

B A

'

(206)

c-5 /\

C-6

c-4

Me

I\

I\

A B

L I

150

I

I

I

I

I

I

I

I

I

100

I

I

a

I

I

50

I

0

b AB

150

100

50

6 (ppm)

FIG. 3. ',C-NMR spectra (270 MHz) of 0.06 M 1,CMDHP (204 and 1,6-MDHP (20b) in CDCI, (lower) and DMSO (upper). Purified solvents were used and the specta recorded at -60°C for CDCI, and at room temperature for DMSO.

0

70

ALEXANDER L. WEIS

[Sec. V.C

d. Kinetic Measurements. Analysis in detail of the kinetics of this tautomeric equilibrium suggests a mechanism for the reaction and allows comparison of the behavior of analogous cyclic and acyclic tautomeric systems. For these measurements, 6-methyl-2,4-dipheny1-1,4-dihydropyrimidine (MDHP) was used because of its relative stability and the near unity of its tautomeric equilibrium constant in aprotic solvents. Preliminary kinetic NMR measurements performed in dried, ultrapure commercial DMSO-d6 were not reproducible, owing to oxidation to 6methyl-2,4-diphenylpyrimidineby the DMS0.’47-’50 Purified CDCl, is more stable, giving reproducible kinetic measurements. Kinetic results obtained by proton-NMR studies of MDHP in CDCl, are based on measurements made by means of standard lineshape analysis applied to H-5.205 Discussed below are theeffects of solute and solvent purity on the rate of the tautomerism, as well as a systematic study of the temperature and concentration dependence of the rate constant.

i. Eflect of solvent purity. The presence of even minute amounts of impurities in the solvent strongly catalyzes the tautomeric equilibration described in Eq. (49)as seen in the so-called “coalescence temperature” (t,) of the H-5 peaks of the A and B species. Various combinations of the solute and solvent were examined, and the coalescence temperatures were determined as a function of MDHP concentration (see Fig. 4). Clearly, purification of both solvent and MDHP has a marked effect on t,. Further recrystallization of the MDHP and distillation of CDCI, produced no further increase of t,. Therefore, such solutions were used for the final kinetic studies.204 The addition of trace amounts of ammonium salts, HCl, or even a drop of commercial CDCl, to the purified solutions of DMSO or CDCl, resulted in complete coalescence of the spectra of tautomers A and B. On the other hand, in CDCl, the addition of equal amounts of water with respect to solute had almost no affect on the rate of tautomerism. ii. Concentration and temperature dependence of k,. The temperature dependence of the ‘H-NMR spectra of MDHP in CDCl, containing different concentrations of solute in the range 10-60 mM and between - 60” and + 60°C is shown in Fig. 5. To determine the effect of concentration on the rate, plots were made of k , versus concentration of MDHP at each

205

H. Gunther,“NMR Spectroscopy-An Introduction,” Chapter VIII. Wiley,Chichester, 1980.

Sec. V.C]

DIHYDROAZINES

71

[MDHP] (rnMl

FIG.4. The coalescence temperature t, for the proton peaks H-5 of MDHP in CDCI, solution as a function of solute concentration. Curves a-d represent successively more highly purified solutions.

FIG.5. 'H-NMR spectra (270 MHz) of 0.073 M 1,CMDHP (20a) and 1,6-MDHP (20b)in CDCI, (highly purified) at different temperatures.

72

ALEXANDER L.WEIS

[MDHP]

[Sec. V.C

(mM1

FIG.6. Plots of k A as a function of MDHP concentration for different temperatures.

temperature (see Fig. 6). At a fixed temperature, k, can be written as the sum of two terms: k , = k , + k2[MDHP] (50) where k , corresponds to a monomolecular reaction yielding A from MDHP, while k2 corresponds to a bimolecular path. At concentrations greater than 60 mM MDHP, k , plots deviated from linearity; this may be due to solubility and aggregation effects. Values for k l and k2 of Eq. (50) were obtained for six temperatures in the range - 35 to +45"C, and Arrhenius plots of these rate constants are given in Fig. 7. The kinetic parameters are: 1. For k,:k,(300 K) = 31 sec-', AHt = 3.9 kcalmol-', and A S = - 43 e.u. 2. For kz:k2(300 K) = 1.0 x lo3 M-' sec-', AH* = 2.7 kcalmol-', and AS: = -41 e.u. Two mechanisms are involved in the transformation between tautomers: one is first order with respect to MDHP concentration, while the other is second order. The first-order reaction involves the solvent in a proteolytic reaction: MDHP

+ Sol

ki

Sol H + + MDHP-

(51)

where in the reverse reaction, the protonation may take place at the second nitrogen. This process may also proceed with remnant impurities still present in the solution; these may serve as conjugate bases to the MDHP molecules. Therefore, the observed k l must be considered as an upper limit for the reaction with CDCl,. The second-order reaction is a proton exchange between two MDHP molecules. Alternatively, it may involve proton transfer between MDHP

Sec. V.C]

DIHY DROAZINES

73

FIG.7. Arrhenius plots for the monomolecular ( k , )and bimolecular ( k 2 )rate constants derived from the analysis of the results in Fig. 6.

molecules and either one of the disproportionation products of the selfionization reaction. 2MDHP (MDHP*)

+ MDHP

MDHP++MDHP-

(52)

= (MDHP) + MDHP*

(53) In concentrated solutions (above 20 mM MDHP), the bimolecular reaction dominates, whereas in dilute solutions, monomolecular protolysis prevails.

e. Intra- and Intermolecular Mechanisms of Proton Transfer in Amidines. The proton is easily transferred between atoms of similar electronegativities. In a case where the steric structure of a molecule prevents intramolecular transfer, a proton may take part in intermolecular migration. Migration from one center to another apparently depends on the ability of the molecules to form hydrogen-bonded bridges. Two situations may arise for amidines.

74

ALEXANDER L. WEIS

[Sec. V.C

Free rotation about the C-N bond in acyclic amidines can place the hydrogen attached to the N(sp3)in a very accessible position to the lone pair of the N(sp2),producing intramolecular hydrogen bonding that enables proton migration. In contrast, in cyclic amidines free rotation does not occur, and conformational changes of the ring system cannot lead to intramolecular hydrogen bonding. Only intermolecular proton transfer is possible. Confirming this interpretation is the observation that in cyclic amidines a concentration dependence is observed on the rates of tautomerism, whereas in acyclic systems the proton transfer is independent of concentration. Despite the wide belief that hydrogen transfer between electronegative atoms, such as N or 0,is a very fast process and that the presence of individual tautomers cannot, therefore, be detected on the NMR time scale, it is possible to slow down this equilibration rate by carefully controlling structural factors in a series of DHP. 1. The delocalization of the lone pair of nitrogen electrons will slow down proton transfer to this atom.44 Compounds in which phenyl groups at position 2 of dihydropyrimidines were replaced by methyls or those formed by reducing the conjugated C=C bond to give the corresponding tetrahydropyrimidines (120) show drastically enhanced hydrogen exchange. On the other hand, introduction of a second phenyl at position 6 in compound 121 notably decreased the rate of tautomerization, and separate signals for both isomers were detectable by 'H and "C NMR in CDCl, at rather high concentrations (0.1 M ) and at ambient temperature. This is probably the reason that exchange occurs slowly, if at all, in dihydroquinazolines.

H

H ( 120)

(120)

(121a)

(121b)

2. The steric environment of substituents adjacent to the amidine fragment of dihydropyrimidines (particularly the bulkiness of substituents at the neighboring sp3-hybridized carbon atom) also affects tautomeric exchange. [An analogous situation was found in the dihydro-1,3,5-triazine series (Section VIII,C).] Further investigations are necessary to clarify the mechanisms, particularly 15N-NMRstudies of the annular tautomerism of dihydropyrimidines, the chemical shift data of which enable calculation of the electron

Sec. V.C]

75

DIHY DROAZINES

density on the nitrogens. A correlation of the latter with the rates of tautomerism for a number of variously substituted dihydropyrimidines would be a critical test of the “delocalization hypothesis.”

2. Tautomerism of I ,2-Dihydropyrimidines Successful preparation of 4,6-diphenyl- 1,2-dihydropyrimidine (21a) (Section V,B) stimulated comprehensive spectral studies of this compound.’84 Of particular interest were NMR measurements to verify the presence of homoaromaticity as previously found for dihydrotetra~ine.’~.’~ To facilitate observation of two signals for the protons on carbon 2, measurements were made at - 60°C. However, all attempts to detect homoaromaticity under E

;

f

p4

Ha b

L 7

Ph

Ph

H

H

. Ha H b

(2W

conditions similar to those used for dihydrotetrazines failed. One likely explanation is a significantly faster flipping in the 1,2-dihydropyrimidine ring, which, to freeze, requires even lower experimental temperatures than those investigated. Instead of homoaromaticity in the CDCl, spectra of 4,6-diphenyl-1,2dihydropyrimidine, two new triplets were observed at 6 3.56 (J = 6.6 Hz) and 6 5.79 (J = 6.6 Hz). These were assigned to 4,6-diphenyl-2,5-dihydropyrimidine (21b)(Fig. 8), the second tautomeric form of the imine-enamine tautomeric equilibrium. The ratio of 21a to 21b is 2:l. In DMSO-d, solution, the equilibrium shifts completely toward 1,2-dihydropyrimidine 21a because of strong intermolecular hydrogen bonding with the solvent. An analogous effect was observed in 1,6-dihydropyra~ine.~~ Ph I

H.

‘O=S

/Me ‘Me

76

[Sec. V.C

ALEXANDER L. WEIS H

H-5 A

H-5

B

H-2

B

Y

i

8

5

6

4

3

FIG.8. 270-MHz 'H-NMR spectrum of 4,6-diphenyl-l,2-dihydropyrimidine(214 in CDCI,

c-5 A

c-2 A CDCIJ

c-5 B I

160

I

150

I

I

140

130

I

120

I

110

I

I

I

I

I

I

100

90

80

70

69

50

I

40

I

30

6 (pprn) FIG.9. 67.9-MHz 13C-NMR decoupled spectrum (lower trace) and coupled spectrum (upper trace) of 4,6-diphenyl-1,2-dihydropyrimidine(214 in CDCI, . Peaks A correspond to the 1,2dihydro and peaks B to the 2,s-dihydro tautomers.

I

2C

Sec. V.D]

DIHYDROAZINES

77

Existence of this imine-enamine tautomerism is clearly indicated in the "C-NMR spectrum of 21a in CDCl, (Fig. 9). A simple calculation using the concentrations of the two tautomers in CDCl, gives the value of A G O in this solvent as 0.41 kcal mo1-'.'84 Unsymetrically substituted 1,Zdihydropyrimidines undergo tautomeric equilibration via [1,5]-hydrogen shift.49

D. PHYSICOCHEMICAL PROPERTIES 1. Infrared Spectra

'

All N-substituted dihydropyrimidines absorb in the 3100-3500 cmregion and show the characteristic stretching modes for bonded and nonbonded N-H groups. The number and position of these depend on structural factors and on the conditions of measurements. The N-H stretching frequencies have been reported for a wide variety of N-substituted tautomeric 1,4- and 1,6-dihydropyrimidines; the absorptions, which are of medium intensity, appear for solutions in the 3360-3490 cm-' region,23.24.144.152.156,175.176.187 IR spectroscopy has been used to study the association of such compounds.206Thus in dilute chloroform solution (0.005 M), the dihydropyrimidine 20 shows a sharp absorption at 3450 cm-' attributable to nonassociated N-H; in a more concentrated solution (0.5M) and in the solid state, the compound displays in the former a broad signal at 3320 cm-' and in the latter at 3100-3240 cm-', owing to intermolecularly hydrogen-bonded N-H.'06 The N-H stretching frequencies of N-unsubstituted 1,2-dihydropyrimidinesgenerally appear in the region 3380-3450 ~ r n - ' . ' ~ ~ All dihydropyrimidines show absorptions in the region 1500-1700 cmwhich are assigned to the C=C or C=N stretching modes. As was mentioned in Section V,C,l,a, the IR absorption bands in the region 1600-1700 cm-' provide an excellent tool for differentiating between tautomeric 1,4- and 1,6-dihydropyrirnidine~~~~~~*~~~ since the C=N stretching band of the 1,4 tautomers has been consistently observed 30-60 cm-' higher than the corresponding band of the 1,6 tautomer, and the intensity of these peaks correlates with the ratio of tautomers in solution. By introducing a phenyl group at position 2 of these dihydropyrimidines, the C=N absorptions of both tautomers are shifted to higher frequencies by -20-30 cm-'. On the basis of these data, the existence of two tautomers was found for all synthesized N-unsubstituted 1,4-and 1,6-dihydropyrimidines by analysis of The C=N absorption of 1,2-dihydropyrimpublished IR data.' idines usually appears in the 1595-1630 cm-' region.'84 A similar IR

',

75*1769187

*06

A. L. Weis, unpublished results.

78

ALEXANDER L. WEIS

[Sec. V.D

tendency was observed by Kashima and c o - ~ o r k e r s ' ~ ~ "for isomeric compounds 110, 111, and 112 in the region 1600-1700 cm-', with the frequencies decreasing in the order 111 > 112 > 110. Undoubtedly, IR spectroscopy provides important structural information and, therefore, needs more systematic study.

2. Ultraviolet Spectra Surprisingly few publications contain UV spectral data on dihydropyrimdespite the paucity of examples, one can i d i n e ~ . ' ~ ~ - ' ~ ~ *However, ' easily distinguish the following characteristic absorption bands for different types of dihydropyrimidines. Thus 1,4-dihydropyrimidines display n + n* transitions for the C=C-N-C=N chromophore, which appears as a medium intensity band ( E 6500) in the 250-260 nm region. The introduction of an aryl group at positions 2 and/or 4, as well as an alkoxycarbonyl group at position 5, shifts the absorption to a longer wavelength and increases its intensity. The UV spectra of 1,6-dihydropyrimidines usually appear at a higher wavelength than their corresponding 1,4 isomers and display an n + n* transition for the C=C-N=C-N chromophore, which appears as a This medium intensity absorption ( E 5000) in the 300-320 nm absorption also depends on substituents and the solvents. This difference in UV absorption of tautomeric 1,4- and 1,6-dihydropyrimidines may be used for quantitative study of amidinic tautomerism of dihydropyrimidines, as well as for assigning structures. The longest wavelength absorption appears in 1,2-dihydropyrimi d i n e ~ , ' ~ ~ , ' which ~ ~ ~ 'is~ clearly ~ . ' ~ ~the result of an n + n* transition involving the N-C=C-C=N chromophore. In general, such compounds show absorption maxima at 340-350 nm, and are usually of medium intensity (E 6000). 1,4-Didhydropyrimidines are usually colorless substances, whereas most of the 1,6- and 1,2-dihydropyrimidines are yellow. 899200

-

-

-

3 . Nuclear Magnetic Resonance Spectra The use of 13C NMR has as yet received only sporadic attention,106*189*203*204 although this area, as well as 15N NMR, is expected to develop rapidly over the next few years. The olefinic proton at position 5 of 1,4- and 1,6-dihydropyrimidines resonate in the region 6 4.205~00~23.24,144,152,156,17 5.176, I8 5-1 89,200 When separate 'H-NMR signals of both tautomers or N-substituted isomers can be observed, the signal for the 1P-dihyd1-0 compound appears 0.4-0.6 ppm upfield from that for the 1,6-dihydro isomer. As can be seen in Figs. 1 and 2, signals for pro-

Sec. V.D]

79

DIHY DROAZINES

tons at position 4 are not usually affected by hybridization of the adjacent N atom. The protons at position 5 in 1,2-dihydropyrimidines usually appear at 6 5.2-5.4 lower than corresponding 1,4- and 1,6-dihydro isomers.49,161,162,164-167.1 84,188,189,199 NH proton shifts depend on the polarity of the solvent used and usually appear in CDCl, at 6 5.6-6.8, in dioxane at 6 6.5-7.5, in acetone and DMSO at 6 7.8-8.6, and in HMPA at 6 9.0-9.6. Interesting regularities can be deducted from 13C-NMR spectra. Thus the s p 3 carbons in dihydropyrimidines usually appear in the 50-70 ppm region, whereas the carbons at position 5 appear at 6 100-108.'88~189~203~204 Comparison of the available data for 13C-NMR shifts in tautomeric dihydropyrimidines (see Section V,C) and in isomeric N-phenyl- 1,4-,- 1,6-,and -1,2-dihydropyrimidines indicate203*204 that C-5 in the 1,4isomer appears at a higher field than that in the 1,6 isomer, but at a lower field than that in 1,2dihydro compounds. Signals of saturated ( s p 3 )carbons, on the other hand, give shifts to higher field in the order 1,6- > 1,4- > 1,2-dihydropyrimidines. A detailed analysis of 'H- and 13C-NMR spectra of 1,2-dihydropyrimidinium salts was reported.161*'84 Both authors assumed that the 2-position in these salts lies out of the plane of the conjugated portion of the molecule. However, attempts to observe possible inversion in this system produced no change in the 'H-NMR spectrum of 122 down to -60°C [Eq. (54)]. Et

Et

4. Crystal Structure X-Ray diffraction examination of the molecular stru.cture of 1,6-,', 1,4-,24 and 1,2-dihydropyrimidines' not only provides the bond lengths, angles, and conformations of these isomers, but also serves as an instrument for unambiguous structural assignment (Section III,E,l). The crystal structure of each of these compounds demonstrates the presence of an intermolecular N H - N hydrogen bond. Molecular association through the N H * * * N hydrogen-bond bridge is undoubtedly one of the major factors responsible for the fact that, as a rule, N-1-unsubstituted

80

[Sec. V.E

ALEXANDER L. WEIS

1,6-, 1,4-, and 1,2-dihydropyrimidines are solids, whereas N-substituted are liquids. derivatives,188s189as well.as 2,5-dihydropyrimidine~,'~~.'~~ Dihydropyrimidines in which the NH hydrogen is available for intermolecular hydrogen bonding are soluble in polar and rather insoluble in nonpolar solvents (as CCI,, hexane, or cyclohexane). When dihydropyrimidines are substituted in position 1, the solubility characteristics are reversed.

E. REACTIVITY The most important reaction of dihydropyrimidines is their oxidation to the corresponding pyrimidines (via dehydrogenation, hydrogen transfer, or disproportionation). However, although many such oxidations have been carried out, they were aimed at enabling identification of dihydropyrimidines from the pyrimidine formed, rather than a study of the kinetics and mechanism of the oxidation reactions themselves. Thus besides spontaneous oxidation in air, 1,4(1,6)-dihydropyrimidines were oxidized by KMnO, ,152.1 55.156.17 1-1 73 DMS0,147-151 , 1 5 3 or potassium he~acyanoferrate(II1)'~~; 1,2-dihydropyrimidines were oxidized by KMn04,175,176,178,183,184 DMS0,163 or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).'99 1,4-Dihydropyrimidine(20) easily reduces some a,P-unsaturated ketones to saturated ketones (for example, chalcone, benzylacetone, benzilideneacetylacetone, and maleic anhydride), as well as some activated carbonyls, such as trifluoroacetone, pyruvic acid, and phenyl glyoxylate. This important property of dihydropyrimidines needs further thorough quantitative investigation. Tautomeric 1,4- and 1,6-dihydropyrimidines easily undergo nucleophilic addition. For example, upon prolonged contact with moisture, the addition of water across the C=C bond, with quantitative formation of 6-hydroxy1,4,5,6-tetrahydropyrimidines,was observed [Eq. (55)]. The products are identical to those obtained by interaction of a,P-unsaturated carbonyl compounds with amidines and indicate the reversibility of the dehydration step in the course of dihydropyrimidine formation for 6-hydroxytetrahydropyrimidines (Section V,B,l).

H

H

Very little work has been published on the thermolytic reactions of dihydropyrimidines, a field which should produce interesting results. When

Sec. V.E]

81

DIHYDROAZINES

1,6-dihydropyrimidine 122 was heated at 210"C, ammonia was evolved, and pyrolytic rearrangement gave 2,4,6-triphenylpyridine.207A plausible mechanism for this rearrangement has been proposed (see Section VII1,E). A new synthesis of pyrimidines substituted at position 5 was reported by van der Stoel and van der Plas"5~'76*208via photochemical rearrangement of 4-substituted 1,4(1,6)-dihydropyrimidines (100) to the corresponding 5substituted 1,2-dihydropyrimidines (125), which on oxidation yielded 5substituted pyrimidines [Eq. (56)].

(100)

(125)

The authors postulated a di-n-methane mechanism for the photochemical isomerization, with the formation of 2,4-diazabicyclo[3.1 .O]hex-2(3)-ene(123) as an intermediate. Subsequent opening of the three-membered ring with a concomitant [1,5]-hydrogen shift from nitrogen to C-2 gave 2,5-dihydropyrimidine 124 [Eq. (57)].

(100)

(123)

(124)

( 125)

Although the 2,5-dihydropyrimidines (124) could be neither isolated nor detected by spectroscopic means, the migration of hydrogen attached to nitrogen in 123 to the adjacent C-2 (124) was demonstrated by irradiating '07

L. S. Cook and B. J. Wakefield, Tetrahedron Lett., 1241 (1979). R. E. van der Stoel, H. C. van der Plas, and G .Geurtsen, J . Heterocycl. Chem. 17,1617 (1980).

82

ALEXANDER L. WEIS

[Sec. VI

an N-1-deuterated analog of 123. Oxidation of the photolysis mixture gave 4,5-diphenylpyrimidine containing 56.5% deuterium at (2-2, the amount expected for a homo[l,S]-deuterium shift from nitrogen to C-2. Moreover, spectroscopic evidence for the intermediacy of a 6-substituted 2,4diazabicyclo[3.1.0] hex-2(3)-ene in this photoisomerization was presented.208 The isolation of 1,2-dihydropyrimidines (125) failed because of their instability, and, therefore, evidence for structure 125 was based on spectral and chemical data. Thus heating of the crude irradiation mixture in air or its oxidation with potassium permaganate gave 5-substituted pyrimidines.' Finally, by irradiation of 1,4(1,6)-dihydropyrimidines (100) containing electron-withdrawing substituents at position 4,a photochemical ring contraction to imidazoles 126 was observed.208 'vl

a: b: c: d:

''

R ' = 2-thiazoly1, R 2 = H R ' = 2-pyridyl, R 2 = H R ' = 4-pyridyl, R 2 = H R ' = 2-pyridy1, R 2 = Ph

A 2-thiazolyl or 4-pyridyl group in position 4 causes an exclusive photoinduced ring contraction to an imidazole (126). 2-Pyridyl substitution leads to both an imidazole (126) and a 5-substituted 1,2-dihydropyrimidine (125), whereas a phenyl group in position 4 yields only 125. Lloyd and McNab investigated the behavior of 1,2-dihydropyrimidinium salts in reactions with different electrophilic and nucelophilic reagents and concluded that these dihydropyrimidinium compounds present an intriguing example of dihydro "aromatic" compounds, which show much greater reactivity toward electrophilic substitution than do the parent aromatic compounds.'

''

VI. Dihydro-1,2,3-triazines At present, available data on dihydro-1,2,3-triazines is limited. Although reduction of 4,5,6-triphenyl-l,2,3-triazine (127a) with zinc in acetic acid or with hydrogen over palladium affords 3,4,5-triphenylpyrazole ( 130),209the *OY

E. A. Chandross and G . Smolinsky, Tetrahedron Lett., 19 (1960).

Sec. VII.A]

83

DIHYDROAZINES

reduction of triaryl-1,2,3-triazines (127a) with lithium aluminum hydride,2l o as well as catalytic hydrogenation (Pd-C)211 of the triazines (127b-d), yields, in an almost quantitative yield, dihydro-1,2,3-triazines,which are best identified as the 2,5-dihydro isomers (129a-d) [Eq. (59)].

2,SDihydro- 1,2,3,-triazines(129b,c)were also prepared in reasonable yield by sodium borohydride4 (in MeOH) or catalytic (H, ,Pd-C) reduction2 of 4,6-disubstituted 1,2,3-triazine 2-oxides (128b,c). The structures of 2,5-dihydro-1,2,3-triazineswere supported by ‘H-NMR spectroscopy. Thus the proton attached to N-2 appears in the range 6 8.3-9.02 and methylene protons at position 5 appear at 6 2.45-2.80 ppm. The singlet form of the signal of these protons indicates fast ring inversion of the compound. ‘3’’

VII. Dihydro-l,2,4-triazines

A. GENERAL COMMENTS Of the eight isomeric structures theoretically possible for dihydro- 1,2,4triazines (Section III,A), the best known are the 43- (12h) and 2,5-dihydro derivatives (12e). Surprisingly, no thorough study of the structures of

’lo

A. Neunhoefer and P. F. Wiley, in “The Chemistry of Heterocyclic Compounds” (A. Weissberger and E. C. Taylor, eds.), Vol. 33. Wiley (Interscience), New York, 1978. A. Ohsawa, H. Arai, H. Ohnishi, and H. Igeta, Chem. Commun., 1182 (1980). H. Arai, A. Ohsawa, H. Ohnishi, and H. Igeta, Heterocycles 17, 317 (1982).

84

ALEXANDER L. WEIS

[Sec. VI1.B

dihydro-1,2,4-triazines is available.210Therefore, the structures of dihydro compounds in the following discussion are written as proposed by the original authors (usually, the 4,Sdihydro isomer), but it should not be assumed that these structures have been unambiguously established. In addition, data on possible amidinic tautomerism of 43- and 2,5-dihydro isomers have not yet been reported in the literature. The parent compounds of dihydro-1,2,4triazine are also unknown.

B.

SYNTHESIS

1. Cyclization Methods

a. From N-Acylamino Ketones. N-Acylamino ketones (131)can be treated with hydrazine to form dihydro-1,2,4-triazines (132)d i r e ~ t l y ~ ' ~ or- ~ ' ~ to produce N-acylaminohydrazones (133),2179218The latter are easily transformed to 132 by treatment with hydrochloric acid [Eq. (60)].

C. M. Atkinson and H. D. Cossey, J . Chem. Sac., 1805 (1962). R. Metze, Chem. Ber. 91, 1863 (1958). V. Sprio and P. Madonia, Gazz. Chim. Ital. 87,992 (1957). * I 6 V. Sprio and P. Madonia, Ann. Chim. (Rome) 49,731 (1959). 2 1 7 H. Hagiwara, Y. Oka, Y. Hara, S. Yuguri, J. Susuki, K. Furuno, and I. Iida, Takeda Kenkyusho Nempo22,1(1963) [CA 60, 12011d(1964)]. K. Masuda, Yakugaku Zasshi 81,533 (1961). 214

Sec. VII.B]

85

DIHYDROAZINES

The N-acylamino ketones (131) can be converted by reaction with phosphorous pentachloride to the chlorimine derivative 135, which undergoes further cyclization to 132 by reaction with hydrazine.’ l 9

b. Other Cyclizations. 2,5-Dihydro-3,5,6-triphenyl-1,3,5-triazine (137a) was isolated from the reaction of benzaldehyde azine (136) with potassium tert-butoxide in toluene.’’0 A self-condensation mechanism has been proposed involving 1,Caddition of an azine molecule to the C=N bond of a second azine. Ph

I

bN

Ph

I

CH N+ 2 1 N %CH

-

\N//c,

Ph, ,Ph H C J +CH t

GA

Ph

I

p ~ ~ N ~ H p(61) h Ph N’

Ph (13711)

Tsuge et al. reported the thermal cyclization of 1,6-diazido-2,5-diphenyl3,4-diazahexadi-2,4-ene (138) to 2-azidomethyl-3,6-diphenyl-2,3-dihydro1,2,4-triazine (139) in boiling Irradiation of the latter gives 3,6diphenyl-4,5-dihydro- 1,2,4-triazine (140) [Eq. (62)]. Ph

-

NH

ff”TpH2”3

Ph

N’

-

H N

Ph

(62)

‘N/

2. From 1,2,4-Triazine Derivatives a. Reduction of I ,2,4-Triazines. Early publications report the reduction of 1,2,4-triazines to dihydro- 1,2,4-triazines, using zinc and acetic Japanese Patent 65/4,638 (1965) [ C A 63,5661h (1965)l. J.T.A. Boyle, M. F. Grundon, and M. Scott, J.C.S. Perkin I , 207 (1976). 221 0.Tsuge, H. Samura, and M. Tashiro, Chem. Lett., 1185 (1972).

219

86

ALEXANDER L. WElS

[Sec. VI1.B

or catalytic hydrogenation on Raney nickel. More recently, quantitative reduction with sodium borohydride of 3-methoxy- or 3methylthio-5,6-diaryl-l,2,4-triazinesto the corresponding dihydro-1,2,4Although in the initial p ~ b l i c a t i o n , ’ ~ the ~ triazines was authors described the products as 4,5-dihydro-l,2,4-triazine derivatives, later, based on X-ray analysis,33 they revised this assignment to the 2,5-dihydro1,2,44riazine structure (141) [Eq. (63)].

b. From 1,2,4-Triazines or 1,2,4-Triazinones and Grignard Reagents. 4,5-Dihydro-1,2,4-triazines were also obtained from the reaction of 1,2,4-triazineswith Grignard reagents by nucleophilic addition across the C=N b ~ n d . ’ * ~ - On ’ ~ ~the other hand, the dihydro-1,2,4-triazines isolated from a reaction of 1,2,4-triazin-3-one or 1,2,4-triazine-3,5-dionesZ3’ with a Grignard reagent were ascribed as 2,3-dihydro isomers (142) [Eq. (64)].

c. Electrochemical Reduction. Pinson and co-workers reported that electrochemical reduction of 1,2,4-triazines leads to unstable 1,Cdihydt-o derivatives (143) which rearrange either to a 1,2- (144) or a 43-dihydro P. V. Laakso, R. Robinson, and H. P. Van drewala, Tetrahedron I, 103 (1957). R. Metze and G . Scherowsky, Chem. Ber. 92,2481 (1959). 22 4 C. M. Atkinson and H. D. Cossey, J . Chem. Soc., 1628 (1963). T. Sasaki, K. Minamoto, and K. Harada, Heterocycles 10,93 (1978). 2 2 6 T. Sasaki, K. Minamoto, and K. Harada, Tetrahedron Lett., 1529 (1980). 2 2 7 T. Sasaki, K. Minamoto, and K. Harada, J. Org. Chem. 45,4587 (1980). 2 2 8 T. Sasaki, K. Minamoto, and K. Harada, J . Org. Chem. 45,4594 (1980). 229 J. Daunis and C. Pigiere, Bull. SOC.Chim.Fr., 2493 (1973). 230 J. Daunis and R. Jacquier, J . Heterocycl. Chem. 10,559 (1973). J. Daunis, L. Djouai-Hifdi, and H. Lopez, J. Heterocycl. Chem. 16,427 (1979). 232 A. Mustafa, A. K. Mansour, and H. A. A. Zaher, J. Prakt. Chem. 313,699 (1971).

222

223

”’

Sec. VII.B]

87

DIHYDROAZINES

compound (137b).233 These derivatives can be further reduced to an imidazole (145) or a tetrahydro-1,2,4-triazine(146) [Eq. (65)].

d. Other Methods. Busch and Kiispert have shown that hydrolysis Of 4amino-2,3,4,5-tetrahydro-1,2,4-triazines by treatment with hydrochloric acid produces dihydro compounds, which were formulated as derivatives of 2,3dihydro- 1,2,4-triazine (147).

34

NH2 I

( 147)

A number of dihydro-l,2,4-triazines were prepared by alkylation of the corresponding 1,2,4-triazinone~.~~~~~~~

3 . From Other Heterocycles Shvaika and Fomenko demonstrated the formation of 4,Sdihydro- 1,2,4triazines (149) from recyclization reactions of 1,3-oxazolium salts J. Pinson, J.-P. M'Packo, N. Vinot, J. Armand, and P. Bassinet, Can. J . Chem. 50,1581 (1972). M. Busch and K. Kiispert, J . Prakt. Chem. 144,273 (1936). 235 A. Comparini, A. M. Celli, F. Ponticceli, and P. Tedeschi, J . Heterocycl. Chem. 15,1271 (1978). 2 3 6 0. P. Shvaika and B. F. Lipnickii, Zh. Obshch. Khim. 51,1842 (1981). 233 234

88

[Sec. VI1.C

ALEXANDER L. WEIS

1,3-thiazolium (148b),237*238 or 1,3-selenazolium salts (148~)'~'with hydrazine [Eq. (67)].

R3

a: X = O b: X = S c: X = Se

An interesting ring contraction to form dihydro-l,2,4-triazine (151) was reported by Halladin and HassnerZ4' by the reaction of 1,4-oxazepin-7-ones (150) with hydrazine [Eq. (68)]. H Ph

Ph,HC

(68)

Ph Ph

C. PHYSICOCHEMICAL PROPERTIES 1. Infrared Spectra The N-H stretching vibrations of 4,5-dihydro-1,2,4-triazinesusually appear at 3250-3260 cm1-1,2333239 with the C=N absorptions being found in the 1620-1680 cm-' region.239 The N-H stretching band of the 1,2~~ dihydro compound (144) displays two peaks at 3180 and 3380 ~ m - ' . ' The C=N absorption bands in the 2,5-dihydro compounds were found at 16451650 cm-'. 0.P. Shvaika and V. I. Fomenko, Dokl. Akad. Nauk SSSR 200,134 (1971). 0. P. Shvaika and V. I. Fomenko, Khim. GeterotsikL Soedin., 635 (1976). 239 0.P. Shvaika and V. I. Fomenko, Zh. Org. Khim. 10,2429 (1974). 240 M. J. Halladin and A. Hassner, J . Org. Chem. 38,3466 (1973). 237

238

Sec. VII.C]

89

DIHYDROAZINES

2. Ultraviolet Spectra The UV spectra of a large number of 3-methoxy- and 3-methylthio-4,5In general, such dihydro-1,2,4-triazines (152) have been determined.227*229 compounds show two or three absorption maxima at 214-235,252-296, and 326-360 nm. The short-wavelengthabsorption is usually of medium intensity (E lO,000), although it is sometimes the strongest band. The second band, at -270 nm, is less intense (E -6000) and obviously is the result of n + K* transitions in the MeX-C=N-N=C structure. The long-wavelength absorptions that sometimes appear at 340 nm are usually the weakest band ( E -2000), the result of n + K* transitions in the N-C(OMe)=N-N=C chromophore. These latter absorptions strongly depend on delocalization of the ring K electrons and the lone-pair electrons of N-H, i.e., on the planarity of the N-C=N-N=C fragment of the potentially homoaromatic molecule. Recently, the UV spectra of a series of 3-methoxy- and 3-methylthio-2,5In general, these dihydro-l,2,4-triazines have been reported.227*228*231*23s compounds show only one absorption maximum, in the region 240-270 nm (E 2000-5000). According to Sasaki et a1.,227*228 the hypsochromic shift in the UV absorptions of the similarly substituted 2,5-dihydro-1,2,4-triazines, relative to that of the 4,5-dihydro-1,2,4-triazines,indicates less extensive conjugation of the former, and confirms the insulation of both double bonds. Interestingly, introduction of a phenyl group in position 6 of 2,5-dihydro1,2,4-triazinesproduces a new maximum in the UV spectra, at 300 nm and with medium intensity (E 1200).In addition, a hypsochromic shift of the first absorption band was observed (230-250 nm), with a significant increase in intensity ( E 20,000).

-

-

-

-

-

-

-

3 . Nuclear Magnetic Resonance Spectra The NMR spectra of a number of 4,5-dihydro-1,2,4-triazineshave been reported, the proton at position 6 absorbing in the 6 6.57-7.12 region.227-229*239 The chemical shift of the proton at position 5 depends on the substituent at this position; in the case of methyl, it resonates at 6 3.483.66, whereas phenyl induces a significant downfield shift to 6 4.50-4.70. The proton at position 6 of 2,5-dihydrotriazines appears at 6 6.666.80,227,228 whereas that at position 5 in the case of methyl appears at 6 3.70The downfield shifts of the 3.90, and in the case of phenyl at 6 4.70-5.20.222*235 resonance of position-5 protons in 2,5-dihydro compounds, relative to 43dihydro, results from the presence of adjacent double bonds in the former molecules.227The NH signals of 2,5-dihydro-1,2,4-triazinesappear as a broad singlet at 6 7.70-8.20. The vicinal coupling constants of the 5- and 6-protons of both 2,5- and 4,5-dihydro derivatives are between 1.9 and 2.5 H2.227

90

[Sec. VI1.D

ALEXANDER L. WEIS

D. REACTIVITY When 2,5-dihydro-3,5,6-triphenyl-1,2,4-triazine (137a) was refluxed in toluene with potassium tert-butoxide, rearrangement occurred to give 2,3,4triphenyl-1,3,5-triazine(153)and its 1,Zdihydro derivative (154b).However, if less than 1 equivalent of base is used, the 1,2,4-triazine is obtained along with the 1,3,5 isomer (153).220A novel photochemical ring contraction by protonation and photolysis of 173a to yield 3,4,5-triphenylpyrazoles(155)was reported [Eq. (69)].241

(155)

Ph

Ph

( 153)

(1 W

Sasaki and co-workers have reported the thermal reaction of 5,6-diaryl-

2,5-dihyro-l,2,4-triazines(141) with dimethyl acetylenedi~arboxylate.~~~ Following an initial incorrect assignment of the products,225detailed X-ray diffraction has shown that the substances produced are derivatives of 3,4,7triazabicyclo C3.3.01 octa-2,7-dienes (156)’

’

MeO,C

4

a: X = O Y = H b: X = S ; Y = H c: X = O Y = M e d: X = S ; Y = M e

241

242

e: X = O Y = O M e I: X = S ; Y = O M e g: X = O Y = C I

J. Nagy and J. Nyitrai, Acta Chim. Acad. Sci. Hung. 109, 1 (1982). T. Sasaki, S. Eguchi, K. Minamoto, and M. Ohno, Kenkyu Hokoku-Asahi Garasu Kogyo Gijutsu Shoreikai 39,97 (1981) [ C A 97,216069e (1982)l.

Sec. VIII.B]

DIHYDROAZINES

91

VIII. Dihydro-l,3,5-triazines A. GENERAL COMMENTS Because of the high degree of symmetry of 1,3,5-triazines,only two dihydro isomers are possible: 42- (13a) and 1,4- (13b). It should be noted that the majority of (if not all) known dihydro-1,3,5-triazines bear at least two aryl or polyfluoroalkyl groups, substituents which probably stabilize the compounds. The simple dihydro-1,3,5-triazines containing only alkyl substituents, or just hydrogen, are at present unknown. Despite the recent discovery that Nunsubstituted dihydro-1,3,5-triazines usually exist in a tautomeric equilibrium of 1,2- and 1,Cdihydro derivatives, for purposes of covenience, the dihydrotriazines discussed here will be presented as the structures given in the original literature, still require proper structural study, using modern instrumental met hods.

B. SYNTHESIS 1. From Nitriles One of the first-known synthetic preparations of 1,2-dihydro- 1,3,5-triazines involves trimerization of benzonitrile in the presence of alkali metals or organometallic reagents. In 1896, Lottermoser reported243 that in the presence of sodium, benzonitrile in refluxing benzene produces 2,2,4,6-tetraphenyl-1,2-dihydro-1,3,5triazine (157), sodium cyanide, and 2,4,6-triphenyl-1,3,5-triazine(153) [Eq (7111. Ph

- )!&,,: A

3PhCN

N

+ 153 + NaCN

Ph

H (157)

In support of this structure for 157, it was found that alkaline hydrolysis of the compound gives two molecules of benzoic acid and one molecule of

243

A. Lottermoser, J . Prakt. Chem. [2] 54,132 (1896).

92

[Sec. V1II.B

ALEXANDER L. WEIS

benzophenone. Cook and Jones obtained 157 as the sole product and proposed the following mechanism: initial formation of a phenylsodium intermediate, followed by reaction with three molecules of benzonitrile in a complex addition and cyclization reaction.244On the basis of this mechanism, Anker and Cook studied the action of organolithium reagents on benzonitrile and succeeded in preparing a series of dihydro-1,3,5-triazines (158) [Eq. (72)].245

Swamer ec ul.246 described the formation of 1,2-dihydro-2,4,6-triphenyl1,3,5-triazine(154b)(yield 14%) from benzonitrile in the presence of sodium hydride and proposed a detailed mechanism (Scheme 8), which is, presumably, valid for all trimerizations of nitriles in the presence of organometallic

reagent^.'^^-^^^ PhCN

MB

Ph-C=NM

I

PhCN

Ph-C=N-M

B

I

PhCN

N=C-Ph

I

B Ph I

Ph I N A N

Ph-C=N-M

I N=C-N=C-Ph I

Ph

I

B

(73) Ph

I

P h f i , kH’ , ”

M

M = Metal; B = H, alkyl, aryl

SCHEME8

The optimization of reaction conditions used by Swamer ec a1.246enabled us to prepare 154 in -80% yield.247A spectroscopic study has shown that in A. H. Cook and D. G. Jones, J . Chem. SOC.,278 (1941). R. M. Anker and A. H. Cook, J . Chem. SOC., 323 (1941). 246 F. W. Swamer, G. A. Reynolds, and C. R. Hauser, J . Org. Chem. 16,43 (1951). 24’ A. L. Weis, Is. Chem. SOC.,49th Ann. Meet., 1982, p. 41 (1982). 244 245

Sec. VIII.B]

93

DIHYDROAZINES

solution compound 154 exists in a tautomeric equilibrium between 154a and 154b (see Section VII1,C). The preparation of 154b from aluminum benzaldimine and benzonitrile has been reportedz4’ and rationalized according to Scheme 8. Researchers in Japan have claimed to produce 1,2-dihydro-1,3,5-triazines by high-pressure reactions between aromatic or heteroaromatic nitriles and f~rmaldehyde,’~~ a~etaldehyde,’~~ or ketones25’in the presence of ammonia.

2. From Amidines In 1969, Cherkasov and co-workersz5z showed that the condensation 1,3,5of benzaldehyde with benzamidine gives 2,4,6-triphenyl-1,2-dihydrotriazine (154b) rather than benzylidenebenzamidine (159) (as was reported incorrectly in the early work of PinnerZs3)[Eq. (74)]. Ph

These Soviet workers also prepared a series of 1,Zdihydro-1,3,5-triazines ~’ with by reaction of aryl aldehyde^,'^'^^^^ Shiff b a ~ e s , ’ ~ ~or- ~ketiminesZ5’ amidines of different acids (usually benzoic, trichloro-, or trifluoroacetic). They proposed that the dihydrotriazines form via intermediate azadienes, which undergo cyclization via [4 + 21 cycloaddition, accompanied by elimination of an akylidenimine [Eq. (75)].

H. Hoberg and J. Barluenga-Mur, Justus Liebigs Ann. Chem. 751,86(1971). Japanese Patent 8053,275(1980)[ C A 94,P15775w (1981)l. Japanese Patent 8053,276(1980)[ C A 93,P239469s (1980)l. 251 Japanese Patent 8226,668(1982)[ C A 97,P23825q (1982)l. 2 5 2 V. M. Cherkasov, N. A. Kapran. and V. N. Zavatzkii, Khim. Geterotsikl. Soedin., 350 (1969). A. Pinner, Ber. Dtsch. Chem. Ger. 22,1610(1889). 254 V. M. Cherkasov,N. A. Kapran, V. N. Zavatzkii, and V. T. Tsyba, Khim. Geterotsikl. Soedin., 704 (1971). 2s 5 V. M. Cherkasov and N. A. Kapran, Khim. Geterotsikl. Soedin., 281 (1973). 256 N.A. Kapran and V. M. Cherkasov, Khim. Geterotsikl. Soedin, 995 (1976). N.A. Kapran and V. M. Cherkasov, Ukr. Khim. Zh. 45,862(1979)[ C A 92,6505a (1980)l. 258 V. M. Cherkasov,N. A. Kapran, and Y. L. Yagupolskii, Khim. Geterotsikl. Soedin., 842 (1982). ’08

249

’”

’”

94

ALEXANDER L. WEIS

R>

.R1 R

[Sec. VI1I.B

I

R’

X

= 0, NH, NR

N-Substituted 1,2-dihydro-1,3,5-triazine(160) was prepared by Hunter and Sim via condensation of benzaldehyde with N-benzylbenzamidine [Eq. (76)].259 Ph N A N

1

Ph-N

\Nnph

(160)

Smith et al. demonstrated the formation of 2-aryl-4,6-diphenyl-1,2dihydro- 1,3,5-triazines (154b, 162) by thermolysis of ylides 161 [Eq. (77)] .2 6 o s 2 6 AN&(Me),CH, Ar

PhC<;

NH

-

Ph N A N P’h

N H

k,“,

(77)

(154b: Ar = Ph) (162: Ar = pCH3C,H,)

Moreover, considering the mechanistic similarities between dihydro-1,2triazine formation via ylide thermolysis and the condensation of aryl aldehydes with benzamidine or N-alkylbenzamidines, the [4 + 23 cycloaddition 259

260

D. H.Hunter and S . K. Sim, Can. J . Chem. 50,669 (1972). R. F. Smith, A. S. Craig, L. A. Buckley, and R. R.Solech, Tetrahedron Lett., 4193 (1979). R. F. Smith, R. R. Soelch, T. P. Feltz, M. J. Martinelli, and S. M. Geer, J. HeterocycL Chem. 18, 319 (1982).

Sec. VIII.B]

95

DIHYDROAZINES

proposed by Cherkasov et al. for dihydrotriazine formation is unlikely.262 Thus the mechanistic interpreation first proposed by Hunter and Sim259is preferable, although the formation of triazine through cyclization of intermediate labile gem-diamidine 163 cannot be excluded [Eq. (78)]. Ph

Ar

I

N

P

I

PhYC*NR

+

/

H*N RNkph\

Ph-C\

,N=CHAr /NR

- LNkt N A N

Ph

N-c, Ph H I ,N-C=NR Ar-CH

\N-C=NR H I Ph

H

Ph

-

Ph

I , N=C-NHR ArCH 'N=C-NHR

-

I

Ph

I

R

The unusual reaction of N-haloamidines with enamines to form 1,4dihydro-l,3,5-triazines (164) was investigated and a possible mechanism suggested [Eq. (79)].262

c2, CH

II

C R'

1

R-C-R'

+

'R'

X = CI, Br, I; Y

XNyPh HZN

=

0,CH,

(79)

(164)

1,2-Dihydro-l,3,5-triazines(166) were obtained by interaction of N alkenylimidoyl chlorides (165) with benzamidines followed by chlorination [Eq.

"' L. Citerio, D. Pocar, R. Stardi, and B. Gioia, Tetrahedron 35,69 (1979). 263

T. P. Popovich, A. I. Sedlov, and B. S. Drach, Zh. Org. Khim. 17,2626 (1981).

96

[Sec. VII1.B

ALEXANDER L. WEIS

3. From 1,3,5-Triazines Starting from the 1,3,5-triazines, few syntheses of dihydro-1,3,5-triazines have been reported. Although many versatile synthetic approaches are available, most of them are yet to be tried. The known reactions involve preparation of dihydro-1,3,5-triazine derivatives from 2,4,6-triphenyl-1,3,5triazine (153) via (a) lithium aluminum hydride reduction264;(b) treatment with potassium in tetrahydrofuran, followed by hydrolysis265;and (c) reaction with organolithium compounds and hydrolysis266[Eq. (81)].

W b )

(153)

(1%)

Wakefield and Cook have indicated that the high yield and relative absence of side-products by using organolithium reagents make this reaction advantageous in comparison to trimerization of benzonitrile in the presence of organolithium reagents (Section VIII,A,l). An interesting photochemical formation of different 1,4-dihydro-1,3,5triazines (168-171) was demonstrated by Kobayashi et al.,267who irradiated substituted 1,3,5-triazines(167) of low aromaticity in pentane or cyclohexane, utilizing compounds with two different fluoroalkyl groups on the triazine ring. Two or three distinct products were isolated, the ratio of these dihydro compounds depending on the nature of both substituents and the solvent (which also serves as a reagent) [Eq. (82)].267 H. L. Nyquist, J . Org. Chem. 31,784 (1966). P. Weil and N. Collignon, Bull. SOC.Chim. Fr., 258 (1974). 266 L. S. Cook,G. Prudhoe, N. D. Vernayak, and B. J. Wakefield, J . Chem. Res., Synop., 113 (1982); J . Chem. Res., Miniprint, 1357 (1982). "' Y. Kobayashi, A. Ohsawa, and M. Honda, Chem. Pharm. Bull. 21,1575 (1973). 264

261

Sec. VIII.B]

a CF, b CF3 c CF, d CFZCI

97

DIHYDROAZINES

CF, CF, CFZCI CFZCI

Soh = -,

CF, CFZCI CFzCl CFZCI

4. From I,3,S-Oxadiazines Gambaryan and Zeifman synthesized 1,4-dihydro-1,3,5-triazine(173) by (172) with reaction of 4,4-bis(trifluoromethyl)-2,6-diphenyl-1,3,5-oxadiazine ammonia.26 Ph

(83) Ph

Ph

H

"*

N. P. Gambaryan and Y.V. Zeifman, 120. Akad. Nauk SSSR, 2059 (1969).

98

[Sec. VII1.C

ALEXANDER L. WEIS

Burger et al. have shown that upon thermolysis dihydro- 1,3,5-0xadiazines (174) undergo a retro Diels-Alder reaction with elimination of hexafluo r o a c e t ~ n e . ~The ~ ~ intermediate ~~'~ product, 4,4-bis(trifluoromethyl)-1,3diaza-1,3-diene, was transformed to the corresponding 1,4-dihydro-1,3,5triazine (173) [Eq. (83)].

c. TAUTOMERISM I N DIHYDRO-1 ,3,5-TRIAZINES Dihydro-l,3,5-triazines are of fundamental interest because of their ability to undergo amidinic tautomerism. Furthermore, as these are nitrogencontaining analogues of dihydropyrimidines (methylene at position 5 replaced by N) it would certainly be interesting to compare the effects of nitrogen substitution on the structual stability and tautomeric behavior of these compounds. Kobayashi et aL2" examined chemical shifts in the "F-NMR spectra of [polyfluoro(chloro)methyl]-dihydro-1,3,5-triazines(168-171) in deuteriochloroform and in methanol, concluding that, in these solvents, these compounds exist as an equilibrium between 1,Cdihydro (168a) and 1,2-dihydro tautomers (168b,b'). R' Solv H N X N

I : %

,";(Jv

R*f

R

f

H (1684

- R 2'kNAR3 I

(168b)

~

~

~

3

(168b')

During our investigation on tautomerism in dihydropyrimidines, we measured the IR and 'H- and I3C-NMR spectra of several known dihydro1,3,5-triazines,14' which exist in the solid state as the 1,Zdihydro isomers. The NMR measurements were carried out in two solvents, CDCl, and DMSO, and signals of the two tautomers A and B were always observed. The rate of tautomeric exchange was rather slow, very similar to that in 121, obviously owing to the presence of two phenyls at positions 2 and 4 (see Section V,C,l,d). All the factors affecting amidinic tautomerism in dihydropyrimidines (see Section V,C,l,b) apply equally to dihydro-l,3,5-triazine derivatives. In CDCl, the rate of tautomerism was clearly affected by the bulkiness of the 269

K. Burger and S. Penninger, Synthesis, 524 (1978).

'"K. Burger, S.Penninger, M. Greisel, and E. Daltrozzo, J. Fluorine Chem. 15, 1 (1980). Y.Kobayashi, A. Ohsawa, and M. Honda, Chem. Pharm. Bull. 21,1586 (1973).

Sec. VIII.D]

DIHYDROAZINES

99

(154) R = H (15th) R = Me

( M a ) R = BU substituents on the saturated (sp3)carbon. Thus a change of substituents in the order Bu, Me, H (other reaction conditions being held constant) clearly increases the rate of tautomerism as measured by NMR. IR spectra of dihydro-1,3,5-triazines showed the absorptions similar to those of dihydropyrimidines. Thus two C=N absorption peaks were found for the 1,2- and 1,4-dihydro-1,3,5-triazinesat 1610 and 1640 cm-', respectively. In addition, a reanalysis of the IR data given by K ~ b a y a s h i ~ ~ ' clearly reveals two signals for C=N absorption, at 1680and 1740cm-', which indicates the presence of two tautomeric forms.

D. PHYSICOCHEMICAL PROPERTIES 1. Infrared Spectra Stretching frequencies for the N-H bond have been reported for a wide variety of N-unsubstituted 1,2- and 1,4-dihydro-1,3,5-triazines,the absorptions of which are of medium intensity and appear in the 3380-4430cminterest, however, are the C=N stretching r e g i ~ n . ~ ~ Of ~ . ' particular ~' vibrations, the wave numbers of which are influenced by the substitutents on the doubly bonded carbons. Thus when substitutents are polylfluoroalkyl groups, a strong band is observed in the region 1680-1730 cm-1,267*271 whereas in aryl derivativesthe C=N absorption (which is also strong) shifts to Moreover, reminiscent of a lower frequency (1 605-1680 cm-1).247,258-269*270 the dihydropyrimidines,IR spectra for solutions of potentially tautomeric 1,2display two absorptions due to C=N stretchand 1,4-dihydro-1,3,4-triazines ing frequenciesdiffering by 30-60 cm-1.247*267*271 These, too, can serve as an excellent tool for differentiating between the two tautomers. Thus the absorption at higher frequency relates to the 1,Cdihydro isomer,while the absorption at lower frequency is attributed to the 1,Zdihydrotriazine. The IR spectra of N-methyl derivatives of both tautomers of 173 support this observation.270 Since in the solid state, dihydro-l,3,5-triazines usually exist in only one of the

100

ALEXANDER L. WEIS

[Sec. VI1I.D

two possible tautomeric forms, a comparison of the IR spectrum in the solid with those in solution is usually a facile method for unambiguous structural assignments. Finally, intensity of the absorptions for the two tautomers provides qualitative information about the relative concentrations of the tautomers in solution.

2. Ultraviolet Spectra and Photochromism The UV spectra of 2,4,6-triphenyl-1,2-dihydro-l,3,5-triazines are very similar to those of the corresponding 1,2-dihydropyrimidines (Section V,D,2) and show a strong band at -260 nm ( E -46,000).265 It was briefly reported by L~ttermoser,~~, and then confirmed by von W a l t h e r ~ that ,~~~ TPDT (157) exhibits photochromism in the solid state. H a y a ~ h i , ~who ~, reinvestigated this phenomenon, has shown that TPDT in the solid state has two absorption bands, A,, = 257 and 325 nm (broad, n --t n* transition). On irradiation at 320-380 nm (sunlight or Xenon lamp), TPDT turns brownish pink and shows, in the solid state, A,, = 430; 447, 487, 502, 533, 565, and 584 nm. Moreover, photochromism of TPDT is temperature dependent. According to the these results suggest that the mechanism of photochromism of TPDT is of a new type which he attributes to intermolecular interaction in a crystalline structure, presumably between NH and excited C=N, rather than intramolecular change of the molecular structure.

3. Nuclear Magnetic Resonance Spectra The NMR spectra of several dihydro-1,3,5-triazines have been reported.247'258-263*266-270 Since most of the known compounds of this type bear either aromatic, polychloroalkyl, or polyfluoroalkyl substituents on the triazine ring, 'H NMR is used for the former and "F NMR for the latter derivatives. The main information obtained from 'H NMR concerns the NH and H or alkyl substituents on the sp3 carbon. Thus the NH signals of were found in the region 6 5.1tautomeric 1,2- and 1,4-dihydro-1,3,5-triazines 8.2 in CDCl, and 6 8.0-11.0 in DMSO-d,. The downfield shift of the NH signal in DMSO is caused by intermolecular hydrogen bonds formed between the polar solvent and the solute. Similar to the situation in the dihydropyrimidines, the NH signal of the 1,4-dihydro isomer appears at a lower field than that of the 1,Zdihydro isomer. The proton attached to the saturated 2'2

3'2

R. von Walthers, J . Prakt. Chem. [Z] 67,446 (1905). T. Hayashi, Bull. Chem. Soc. Jpn. SO, 2489 (1977).

Sec. VIILE]

101

DIHYDROAZINES

carbon appears in the region 6 5.2-6.7, depending on the second substituent, which, in the case of an aryl as the second substituent, resonates at 6.2 ppm.

E.

REACTIVITY

In common with other dihydroazines, dihydro-1,3,5-triazines are easily oxidized to the corresponding aromatic triazines when heated or oxidized by various agents such as chlorani1.260*261 Alkylation of dihydro-l,3,5-triazines with dia~omethane”~ and with benzyl chloride259have been reported. Interesting results were obtained by reaction of substituted 1,2-dihydro1,3,5-triazines with esters of acetylenedicarboxylic acid (DMAD) and of propiolic In the case of the reaction with DMAD, formation of the different products 175 and 176 has been reported,254 presumably due to differences in the nucleophilicity of the secondary nitrogen atom of the triazines.

ph

ph l’NJA!=CHCOOEt

A

Ph

Ph

(175)

C0,Me

A1 NC=CH

N’

ANAH

Pr AO,Me

(176)

Furthermore, it was demonstrated that 2-phenyl-4,6-diaryl-1,3,5-triazine reacts with hexafluoro-Zbutyne as a dienophile to give 4,5-bis(trifluoromethyl)-2,6-diarylpyrimidines(177)274[Eq. (84)]. R

R

H

In 1941, Anker and Cook reported that thermolysis of certain alkyldihydrotriazines (158) at 200-250°C gave pyrimidines, with loss of ammonia.245Wakefield and c o - ~ o r k e r s ~ repeated ~ ’ . ~ ~ ~this reaction, confirming the results obtained earlier. They also proposed a mechanism 2’4

N. A. Kapran,V. G. Lukamanov, L. M. Yagupol’skii, and V. M. Cherkasov,Khim. Geterotsikl. Soedin., 122 (1977).

102

[Sec. IX

ALEXANDER L. WEIS

[Eq. (85)] for this transformation [Eq. (85)], involving ring opening accompanied by a 1,3-hydrogen shift, followed by electrocyclic ring closure and elimination of ammonia.207-266 R I

Ph C H

Nx*

N

,‘eR \

R = H, Pr

IX. Conclusions This survey demonstrates clearly that, despite the full century that has passed since the first synthesis of dihydroazines, the chemistry of these compounds remains largely unexplored. Historically, this neglect resulted from insufficiently sophisticated physical and synthetic techniques by which to study these compounds and equally from a widely accepted, though inaccurate, view that these materials are unstable. We now know that, depending on ring substituents, many of these compounds can be highly stable and exhibit interesting variations in chemical reactivity. Because of the multiplicity of possible isomeric forms, depending on the energy state of the system, they may undergo molecular rearrangement, valence isomerizations, or tautomeric equilibria, all of which are of fundamental interest to synthetic and theoretical chemists alike. Moreover, basic properties of these materials, such as stability (redox potentials) or basicity, await detailed examination. Dihydroazines also participate in intra- and intermolecular cyloaddition reactions, which have great potential utility in synthesis and can provide versatile precursors of both known and rare heterocyclic molecules. Some dihydroazines are found in living organisms, and various synthesized analogues can serve as useful models for studying redox reactions involving NADH and flavines. Dihydroazine derivatives also serve as calcium channel antagonists and thus have a considerable future in the area of pharmaceutical

Sec. 1x1

DIHYDROAZINES

103

chemistry. Thus dihydroazines offer a rich source of compounds possessing biological activity as well as interesting chemical and physical properties. We shall probably hear a great deal about them in the years to come.

ACKNOWLEDGMENT The author thanks Dr. Choji Kashima for communicatingexperimental results in advance of publication.

This Page Intentionally Left Blank

ADVANCES IN HETEROCYCLIC CHEMISTRY. VOL. 38

Recent Advances in the Chemistry of Benzisothiazoles and Other Polycyclic Isothiazoles MICHAEL DAVIS Department of Organic Chemistry. La Trobe University. Bundoora. Victoria. Australia

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . I1. 1.2.Benzisothiazoles . . . . . . . . . . . . . . . . . . . . . A. Formation . . . . . . . . . . . . . . . . . . . . . . . 1. From Mercaptophenyl Aldehydes. Ketones. or Acids . . . . . . . 2. From 2.2 '.Dithiobis(benzonitrile) . . . . . . . . . . . . . . 3. From oChloropheny1 Derivatives with Sulfur and Ammonia . . . . 4. From Benzo [b] thiophen-3(2H)-ones and from Thiochromanones . . . 5. Addition of Benzyne to 1.2. 5.Thiadiazole and 1.2. 5.Selenadiazole . . . 6. Reported Formation from an N-Benzylsulfonamide and TrichloromethanesulfenylChloride . . . . . . . . . . . . . 7. From 1H.3H.1. 2.Benzisothiazoline 1-Oxides . . . . . . . . . . B. Physical Properties . . . . . . . . . . . . . . . . . . . . C. Chemical Properties . . . . . . . . . . . . . . . . . . . . 1. Electrophilic Substitution . . . . . . . . . . . . . . . . . 2. Reactions of 3.Chloro.l. Zbenzisothiazole and Related Compounds . . 3. Photochemistry and Photocycloaddition Reactions . . . . . . . . 4. Miscellaneous Reactions Involving Ring Opening . . . . . . . . D. 1.2.Benzisothiazolin.3(2H).ones . . . . . . . . . . . . . . . E. Applications . . . . . . . . . . . . . . . . . . . . . . 111. 1.2.Benzisothiazolin.3(2H ).one 1. 1.Dioxide (Saccharin) and Derivatives . . . A. Formation . . . . . . . . . . . . . . . . . . . . . . . B. Physical Properties . . . . . . . . . . . . . . . . . . . . C. Chemical Properties . . . . . . . . . . . . . . . . . . . . D . Biological Properties . . . . . . . . . . . . . . . . . . . E. Related Compounds . . . . . . . . . . . . . . . . . . . . IV. 2. 1-Benzisothiazoles . . . . . . . . . . . . . . . . . . . . . A . Formation . . . . . . . . . . . . . . . . . . . . . . . 1. From the Corresponding Benzisoxazole . . . . . . . . . . . . 2. By Hydrogen Peroxide Oxidation of o-Aminothiobenzamides . . . . 3. From the Reaction of Thionyl Chloride or Related Compounds with o-Toluidines . . . . . . . . . . . . . . . . . . . . . 4. From Other Nitrogen-Sulfur Transfer Reagents . . . . . . . . . 105

. . 106

. .

107

. .

108 109 109

. . 107 . . 107 . . 108

. .

. .

. . 110

. . 110

. . . .

111 111 . . 111 . . 112 . . 113 . . 114 . . 114 . . 116 . . 116 . . 116 . . 117 . . 117 . . 120 . . 121 . . 122 . . 122 . . 122 . . 122

. .

123

. . 123

Copyright 0 1985 by Academic Press. Inc . All rights of reproduction in any form reserved. ISBN 0-12-020638-2

106

[Sec. I

MICHAEL DAVIS

5. Cycloaddition Reactions of Triphenylthieno[3,4-c]isothiazole 6. Preparation of 2,l-Benzisothiazole 2-Oxides and 2,ZDioxides . . , . . . . . B. Physical Properties . . . . . . . C. Chemical Properties. . . . . . . . . . . . . . . . . . . . . . . 1. Diels-Alder Addition Reactions . . 2. Photochemistry and Thermolysis . . . . . . . . . . 3. Decomposition of 2,l-Benzisothiazolium Quaternary Salts . 4. Reactions of 3-Chloro-2,l-benzisothiazole. . . . . . . D. 2,1-Benzisothiazolin-3(1H)-one. . . . . . . . . . . . 1. Preparation of 2,1-Benzisothiazolin-3(1H)-ones. . . . . 2. Reactions of 2,1-Benzisothiazolin-3(1H)-ones . . . , . . E. Applications . . . . . . . . . . . . . . . . . . V. Other lsothiazole Systems . . . . . . , . . . . . . . . A. Naphthoisothiazoles . . . . . . . . . . . . . . . B. Benzobisisothiazoles and Benzotris[c]isothiazole . . . . . VI. Selenium and Tellurium Analogues. . . . . . . . . . . .

.

.

.

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . 124 . . 125 . . 125 . . 126 . . 126

. . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

126 127 128 128 128 128 129 130 . . . . . . 130 . . . . . . 131 . . . . . . 132

I. Introduction This review, intended to continue the earlier review of benzisothiazoles’ and of benzisosulfonazoles (Saccharin and related compounds),’ covers the period between about 1970 and early 1984. In general, attention has been focused on new results; however, an attempt has been made to be comprehensive. Some parts of this review have received attention elsewhere. For example, a review has appeared on the biological activity of 1,Zbenzisothiazole derivative^,^ thus that topic has received less attention. Until 1980, The Royal Society of Chemistry (previously the Chemical Society) published a section on benzisothiazoles in Specialist Periodical Reports in the volumes on the Organic Chemistry of Sulfur, Selenium, and T e l l ~ r i u mit; ~was then transferred to Heterocyclic Chemistry.’ Saccharin’s use as a sweetening agent has just achieved its centenary. During the 1970s the alleged carcinogenicity in humans of saccharin was the subject of a prolonged controversy. The interested reader should refer to one of the excellent summaries written by Lepkowski.6

’ M. Davis, Adu. Heterocycl. Chem. 14,43 (1972).

’

H. Hettler, Ado. Heterocycl. Chem. IS,233 (1973). A. De, Prog. Med. Chem. 18, 117 (1981). D. H. Reid, “Organic Compounds of Sulphur, Selenium and Tellurium,” Reporter, Vol. 1. Chemical Society, London, 1970; Vol. 2,1973; Vol. 3,1975; Vol. 4,1977; D. R. Hogg, Reporter, Vol. 5, 1979; Vol. 6. Royal Society of Chemistry, London, 1981. H. Suschitzky and 0.Meth-Cohn, “Heterocyclic Chemistry”, Reporters, Vol. 1. Royal Society of Chemistry, London, 1980; Vol. 2, 1981; Vol. 3, 1982. W. C. Lepkowski, Chem. Eng. News, April 11, p. 17 (1977).

Sec. ILA]

POLYCYCLIC ISOTHIAZOLES

107

11. 1,ZBenzisothiazoles

A. FORMATION Since 1970, several new syntheses of 1,Zbenzisothiazoles have been described, and older syntheses have been extended.

1. From Mercaptophenyl Aldehydes, Ketones, or Acids Lawson’ discussed the factors influencing the yields of 1,Zbenzisothiazoles from 2-(alkylthio)phenyl-~ubstituted oximes. This reaction, one of the standard synthetic methods, has been used extensively by a group at the A University of Hull in their syntheses of substituted 1,2-benzi~othiazoles.~ variation involves the formation of a seven-membered heterocyclic ring (1) which is then pyrolyzed to the 1,2-benzisothiazole (2).’

Meth-Cohn and colleagues’ used the tert-butylthio derivatives 3 as useful synthons; the reaction of 3 (R = H) with hydroxylamine, followed by cyclization with polyphosphoric acid, gave good yields of 1,Zbenzisothiazoles. However, in using the nitro-substituted derivative 3 (R = NO2)the tert-butylthio group was cleaved too readily. The resulting thiol odor, being similar to the stenching agent used in town gas, “caused the evacuation of a school half a mile away.” The group was “encouraged to discontinue” their experiments.’ Chloramine is a valuable alternative to hydroxylamine in these reactions and has been used to prepare 7-methoxy-l,Zbenzisothiazole(4; R = MeO) in 70% yield from 2-mercapt0-3-methoxybenzaldehyde.’~

’A. J. Lawson, Phosphorus Sulfur 12,357 (1982). lo I’

IZ

K. Clarke, C. G. Hughes, and R. M. Scrowston, J.C.S. Perkin I , 356 (1973). K. Clarke, B. Gleadhill, and R. M. Scrowston, J . Chem. Res., Synop., 395 (1979) 0.Meth-Cohn and B. Tarnowski, Synthesis, 58 (1978). L. K. A. Rahman and R. M. Scrowston, J.C.S. Perkin I, 385 (1984). L. K. A. Rahman and R. M. Scrowston, J.C.S. Perkin I , 2973 (1983).

108

[Sec. 1I.A

MICHAEL DAVIS

qCHO %Me3

I

R

p i I

R

(5)

(6)

The treatment of a disulfide with ammonia, silver nitrate, and a ketone is a general one-step synthesis of ~ulfenimines.’~ The disulfide 5, in an intramolecular reaction, affords” the 1,2-benzisothiazole6.

2. From 2,2’-Dithiobis (benzonit rile) Oxidation of 2,2’-dithiobis(benzonitri1e)(7) with chlorine affords 3-chloro1,2-benzisothiazole (8).14 This product is a valuable source of other 42benzisothiazoles.

3 . From o-Chlorophenyl Derivatives with Sulfur and Ammonia The previously described synthesis’ from o-chlorobenzylidene chlorides has been extended to the use of o-chlorobenzonitriles,’ o-chlorobenzaldehydes,’ and o-chlorophenacyl compounds.” An example is the preparation

’

l3

l4

l6

’’

F. A. Davis, W. A. R. Slegeir, S.Evans, A. Schwartz, D. L. Goff, and R. Palmer, J . Org. Chem. 38,2809 (1973). J. R.Beck and J. A. Yahner, J . Org. Chem. 43,1604 (1978). H. Fleig and H. Hagen, Ger. Offen, 2,609,864(1977)[ C A 88,6867(1978)l. H.Hagen and H. Fleig, Ger. Offen. 2,503,699(1976)[ C A 85,177401 (1976)l. J. Markert and H. Hagen, Liebigs Ann. Chem. 768 (1980).

Sec. ILA]

POLYCYCLIC ISOTHIAZOLES

109

of 5-chloro- 1,Zbenzisothiazole (9) in 90% yield from 2,5-dichlorobenzaldehyde.16

4. From Benzo[b]thiophen-3(2H)-ones and from Thiochromanones A completely new synthesis of 1,2-benzisothiazoles, developed by a group in Japan, involves the use of o-mesitylenesulfonylhydroxylaminein the presence of base, as in the formation of the lY2-benzisothiazole10 from the thiochromanone 11. The benzo[b] thiophen-3(2H)one 12 is an equally good precursor. l

,-d:

5

QpeO J-.4-\ S

I

+

-0Mes

NH2

5. Addition of Benzyne to I ,2,5-Thiadiazole and I ,2,5-Selenadiazole Benzyne adds to the 1,2,5-thiadiazole or 1,2,5-selenadiazole ring (13; Z =

S or Se), yielding a 1,2-benzisothiazoley or benzisoselenazole, and other products. Is

l9

Y. Tamura,S. M. Bayomi, C. Mukai, M. Ikeda, M. Murase, and M. Kise, Tetrahedron Leu. 21, 533 (1980); Y. Tamura, S . M. M. Bayomi, C. Mukai, M. Ikeda, and M. Kise, J.C.S. Perkin I , 2830 (1980). M. R. Bryce, P. Hanson, and J. M. Vernon, J.C.S. Chem. Commun.,299 (1982).

110

MICHAEL DAVIS

[Sec. 1I.A

6. Reported Formation from an N-Benzylsulfonamide and Trichloromethanesuvenyl Chloride In the previous review’ there was discussed a claim in the patent literature that a 1,2-benzisothiazolinecould be produced from a reaction between an Nbenzyl-substituted sulfonamide and trichloromethanesulfenyl chloride in the presence of base. Reexamination of this reaction has failed to confirm the production of benzisothiazolines.”

I . From 1 H,3H-I ,2-Benzisothiazoline I-Oxides 1H,3H-1,2-Benzisothiazoline1-oxides (14; X = 0, NH) can be prepared from the ester (15; X = OMe) or the amide (15; X = NH2).21*22 If the benzyl chloride (16) is used, the product is 14, which as its hydrochloride yields 1,2benzisothiazole (17) (94%) when heated to 155°C.23

@OX

SMe

I1

X

0

CH2CI U

S

/ i. NaN,/HzS04 ii. base

0

MII e 0

2o 2’

M. Davis and E. Homfeld, Aust. J . Chem. 26, 1365 (1973). P. Stoss and G. Satzinger, Angew. Chem., Int. Ed. Eng. 10, 76 (1971); Chem. Ber. 108, 3855 (1975).

T. R. Williams and D. J. Cram, J . Am. Chem. SOC.93,7333 (1971). 23 R. H. Rynbrandt and D. P. Balgoyen, J . Org. Chem. 43, 1824 (1978).

22

Sec. II.C]

111

POLYCYCLIC ISOTHIAZOLES

B. PHYSICAL PROPERTIES Palmer24 discussed the electronic structure of 1,Zbenzisothiazole in the context of the other aza derivatives of indole, benzofuran, and benzothiophene. The infrared and Raman spectra of 1,2- and 2, I-benzisothiazoles have been recorded, and a complete assignment of the fundamental vibrations pr~posed.’~ The rates of N-methylation and the NMR chemical shifts of the resulting N-methyl salts of isothiazoles, pyrazoles, isoxazoles, and their benzofused derivatives have been examined.26The protonation equilibria of 1,Zbenzisothiazoles have been measured.” In the mass spectrum, breakdown of 1,Zbenzisothiazoles usually results in loss of HCN and CS fragments2*; there is some evidence that the molecular ions from 1,Zbenzisothiazole and from benzothiazole possess a common stru~ture.’~ The crystal and molecular structures of 3-[(2-diethylammonio)ethoxy]-l,2benzisothiazole tetrachlorocobaltate (18) have been determined. The N-S distance is 1.67 A, indicating a small degree of multiple bonding; the N-SC angle is a small 95.1°.30These results are typical of 1,2-benzi~othiazoles.~’ + OCHZCHZNHEI,

e

N

CoCI;

C. CHEMICAL PROPERTIES 1. Electrophilic Substitution

’

1,2-Benzisothiazole undergoes nitration at its 5- and 7-positions. Electrophilic substitution of 3-methyl-l,2-benzisothiazole(2) and its 5-amino, 5M. H. Palmer and S. M. F. Kennedy, J . Mol. Strut. 43,203 (1978). El Jammal, M. Guiliano, J. D. Fourneron, and G. Mille, Phosphorus Sulfur 16,313 (1983). 26 M. Davis, L. W. Deady, and E. Homfeld, Aust. J. Chem. 27,1221 (1974); J . Heterocycl. Chem. l4

” T.

11, 1011 (1974).

A. Braibanti and M. T. L. Mangia, Gnzz. Chim. Ital. 111, 71 (1981). A. Croisy, P. Jacquiqnon, R. Weber, and M. Renson, Org. Mass Spectrom. 6, 1321 (1972). 29 A. Selva and E. Gaetani, Org. Mass Spectrom. 7, 327 (1973); A. Selva, U. Vettori, and E. Gaetani, ibid. 9, 1161 (1974). ’O A. C. Bonamartini, M. Nardelli, and C. Palmieri, Acta Crystnllogr. Sect. B B28, 1207 (1972). 31 E. Gaetani, T. Vitali, A. Mangia, M. Nardelli, ad G. Pelizzi, J.C.S. Perkin 11,2125 (1972). 27

112

MICHAEL DAVIS

[Sec. 1I.C

acetamide, Shydroxy, Smethoxy, Sbromo, and 4-bromo derivatives have been examined in The 3-methyl group can be oxidized to an aldehyde by iodine in dimethyl sulfoxide, or to a carboxylic acid by thionyl chloride followed by alkalisgElectrophilic substitution of 1,2-benzisothiazole-3-acetic acid (19) has been studied.33

2. Reactions of 3-Chloro-l,2-benzisothiazole and Related Compounds Nucleophilic displacement of the chlorine atom of 3-chloro-1,2benzisothiazole has proved to be a popular procedure. Boeshagen and Geiger34have continued their earlier work on nitrogen nucleophiles, and now include carbon, oxygen, and sulfur nucle~philes.~~ In some cases, rearrangements occur, as in the formation of 3-amino-2-acylbenzo[b] thiophenes (20) from reaction of 21 with methyl ketones. Similar results are obtained from the reaction of other carbon nucleophiles, and it has been suggested that attack may be either at the 3-carbon or the sulfur atom.36The reaction of 3-chloro1,2-benzisothiazole (8) with the anion of ethyl cyanoacetate, for example,

K. Clarke, B. Gleadhill, and R. M. Scrowston, J . Chem. Res. Synop., 197 (1980); J . Chem. Res. Miniprint, 2845 (1980). 33 H. Uno and M. Kurokawa, Chem. Phar. Bull. 26,3888 (1978). 34 H. Boeshagen and W. Geiger, Chem. Ber. 109,659 (1976); 112,3286 (1979); 113,2490 (1980). 3 J S. Watanabe, Bull. Chem. SOC.J p n 42, 1152 (1969); S. Huenig, G.Kiesslich, and H. Quast, Justus Liebigs Ann. Chem. 748,201 (1971); H. Boeshagen and W. Geiger, ibid. 764,58 (1972); Chem. Ber. 107, 1667 (1974). 36 D. E. L. Carrington, K. Clarke, and R. M. Scrowston, Tetrahedron Lett., 1075 (1971); J . Chem. SOC.C, 3262 (1971); ibid., 3903. 32

Sec. II.C]

113

POLYCYCLIC ISOTHIAZOLES

affords a 70% yield of the expected product and is a valuable route to other 3substituted compound^.^' A group at the University of Parma, Italy, has made considerable use of these and similar displacement reactions in the synthesis of biologically active compound^.^^ One interesting reaction is the formation of 3-(3-aminobenzo[b]thiophen-2-yl)-l,2-benzisothiazole (22) from the reaction of 3-chloro- 1,2-benzisothiazole(8)with diethyl malonate in the presence of tetraalkylammonium salts. Structure 22 was confirmed by Xray analy~is.~'

3. Photochemistry and Photocycloaddition Reactions Photodecomposition of 1,2-benzisothiazole (17) affords the ring-opened disulfide 7.40If the 3-position is blocked by substitution, then more interesting products may result. Photocycloaddition reactions of 3-phenyl- 42benzisothiazole (23)with alkenes afford excellent yields of 2,3-dihydro-1,4benzothiazepins such as 24.41With electron-rich alkynes, thiazabicycloheptadienes (25) are produced, but no reaction occurs with 2-butyne, 1phenylpropyne, or dimethyl acetylenedi~arboxylate.~~ An analogous S-N bond fission occurs with 2-aryl-l,2-benzisothiazolinones.43

mMe-

Ph

Ph N

7d

N

&>OEt Me

(25r:R = OEt) (25b:R = NEt,) D. E. L. Carrington, K. Clarke, C. G. Hughes, and R. M. Scrowston, J.C.S. Perkin I, 3006 (1972). '* T.Vitali, P. Scnvani, G. Pellegrini, R. Ponci, F. Gialdi, and E. Arsura, Ger. Offen. 1,950,370 (1970)[ C A 73, 130991 (1971)l;M. Gianella, F. Gualtieri, and C. Melchiorre, Phytochemistry 10, 539 (1971);T. Vitali, F. Mossini, R. M. Mingiardi, E. Gaetani, and V. Plazzi, Ateneo Parmense, Acta Anat 7,71 (1971)[ C A 77,56391 (1972)],T.Vitali and L. Amoretti, Boll. Soc. Ital. Biol. Sper. 47,790(1971)[ C A 77,71265(1972)l;C. Branca, D.Serafini-Fracossini, and N. Bagni, Experientia 30,105 (1974);P.V. Plazzi, M. Vitto, C. Branca, and L. Zappia, Ateneo Parmense, Acta Nat. 15,49(1979)[ C A 92,76378(1980)l;P. V. Plazzi, M. Vitto, F. Bordi, and M. Chiavarini, ibid. 18,51 (1982)[ C A 99,447(1983)l. 39 F. Mossini, M. R. Mingiardi, E. Gaetani, M. Nardelli, and G. Pelizzi, J.C.S. Perkin 11, 1665 (1979). 40 M. Ohashi, A. Ezaki, and T. Yonezawa, J.C.S. Chem. Commun., 617 (1974). 41 M. Sindler-Kulyk, D. C. Neckers, and J. R. Blount, Tetrahedron 37,3377(1981). M. Sindler-Kulyk and D. C. Neckers, J. Org. Chem. 48,1275 (1983). 43 N. Karnigata, S.Hashimoto, S. Fujie, and M. Kobayashi, J.C.S. Chem. Commun., 765 (1983). 37

114 4.

MICHAEL DAVIS

[Sec. 1I.D

Miscellaneous Reactions Involving Ring Opening

Boeshagen and Geiger have shown that reduction of 3-dialkylamino- 42benzisothiazoles (26) with thiophenol affords a mercaptobenzamidine (27) which is in equilibrium with dipolar or 1,2-benzothioquinone methide (28).44 Diazotization of 7-amino-1,2-benzisothiazole (29) yields- 1,2,3-benzothiadiazole-7-carbaldehydes ( 3 0 ) : '

D. I ,2-BENZISOTHIAZOLIN-3(2H)-ONES The crystal and molecular structure of 1,2-benzisothiazolin-3-one (31) have been determined. Both C-S and S-N bonds are single.46 Some novel methods of preparation have appeared. One of the most interesting is the Diels-Alder reaction of 4-isothiazolin-3-one 1-oxides (32;

H. Boeshagen and W. Geiger, Liebigs Ann. Chem., 14 (1982). Haddock, P. Kirby, and A. W. Johnson, J . Chem. SOC.C, 3994 (1971). 46 L. Cavalca, A. Gaetani, A. Mangia, and G. Peliui, Gazz. Chim. Ital. 100,629 (1970). 44

" E.

Sec. II.D]

POLYCYCLIC ISOTHIAZOLES

115

n = 1) and dioxides (32;n = 2), which afford reduced derivatives such as 33.47Another is the use of thionyl chloride to cyclize 2-methylsulfenyl- or 2methylsulfinylbenzamides (34;n = 0, 1) to 2-substituted 1,2-benzisothiazolinones (35) in quantitative yield.48 If the diary1 sulfoxide (36)is used instead, then the interesting S(1V) derivative 37 is formed.49 Workers in the Soviet Union have examined oxidative reactions of 31 and have also produced a number of sulfoxide derivative^.^'

acoNHcH d y C H M e 2

so

M e 2 C H\N a 0 (37)

(36)

The nitrogen atom of 31 is readily alkylated. The 2-phenacyl derivative (38) rearranges to 2-benzoyl-2H-1,3-benzothiazin-4(3H)-one (39) in mild base,51 illustrating once again the ease with which the S-N bond is broken.

d y C H 2 C O F ' h

(3)

-

d r c O p h (39)

E. D. Weiler and J. J. Brennan, J . Heterocycl. Chem. 15, 1299 (1978). Y. Uchida and S. Kozuka, J.C.S. Chem. Commun., 510 (1981); Bull. Chem. SOC.Jpn. 55, 1183 (1 982). 49 L. J. Adzima, C. C. Chiang, I. C. Paul, and J. C. Martin, J . Am. Chem. SOC.100,953 (1978). '' E. S . Levchenko and I. N. Berzina, Zh. Org. Khim. 6, 2273 (1970); E. S . Levchenko and T. N. Dubinina, ibid. 14,862(1978); V. N. Klyuev, A. B. Korzhenevskii, and B. D. Berezin, Izu. Vyssh. Vchebn. Zaoed., Khim. Khim. Tekhnol. 21,31(1978) [CA 88, 170041 (1978)l. '' J. C. Grivas, U S . Patent 3,761,489 (1973) [ C A 79, 137126 (1973)l; J . Org. Chem. 40,2029 (1975); 41, 1325 (1976). 47

48

116

[Sec. 1II.A

MICHAEL DAVIS

E. APPLICATIONS The biological activity of 1,2-benzisothiazole derivatives was reviewed in 1981 by De.3 Since then, further claims have been made regarding the auxinlike activity of 3-acetic acid derivative^,^' the analgesic activity of 3-benzyl derivative^,^^*^^ the antithrombogenic activity of 5-chloro-2-alkyl comp o u n d ~ the , ~ fungicidal ~ ~ ~ ~ activity of 3-thio derivative^,^^,^' the antiinflammatory activity of 2-halophenyl derivative^,^' and the diuretic effects” of 1,2-benzisothiazole-6-oxyaceticacid derivatives.

111. 1,2-Benzisothiazolin-3(2H)-one 1,l-Dioxide (Saccharin) and Derivatives

A. FORMATION Few totally new syntheses have been reported. Autoclaving (165”C, 6 hr) of the sulfonyl chloride 40 with sulfur and ammonia gives6’ a moderate yield of saccharin (41). Photolysis of the oxime ether 42 affords N-alkoxysaccharins

OcH’” ‘ d\

N

so*H

SO*Cl

” C.

A. Maggiali, M. R. Mingiardi, M. T. Lugari Mangia, F. Mossini, and C. Branca, Farmaco Ed. Sci. 37,319(1982)[CA 97,18952(1982)];C. Branca, C. A. Maggiali, M. R. Mingiardi, and D. Ricci, J . Plant Growth Regul. 1,243(1982). ” F. Bordi, M. Vitto, P. V. Plazzi, and G. Morini, Ateneo Parmense, Acta Nat. 19,35(1983)[ C A 99,187589(1983)l;G. Morini, M. Impicciatore, F. Bordi, P. V. Plazzi, and M. Vitto, Farmaco, Ed. Sci. 38,794(1983)[CA 99,205623(1983)l. ” T. Vitali, M. Impicciatore, and P. V. Plazzi, Farmuco, Ed. Sci. 37, 674 (1982)[ C A 98, 379 (1983)J Green Cross Corp., Jpn. Kokai Tokkyo Koho 58 177,915(1983)[ C A 100,56845(1984)l. ” H. Hagen, H.Ziegler, and E. H. Pommer, Ger. Offen. DE 3,202,298(1983)[CA 99, 175752 (1983)J ” P. Borgna, L. Vicarini, M. L. Carmellino, and G. Pagani, Farmaco, Ed. Sci. 38,801(1983)[CA 100,19153 (1984)l. ’13 A. Welter, H. H. Lauterschlagen, E. Etschenberg, and S. Leyck, European Patent Appl. EP 51,193(1982)[ C A 97,98360(1982)]. G. M. Shutske, R. C. Allen, M. F. Foersch, L.L. Setescak, and J. C. Wilker, J. Med. Chem. 26, 1307 (1983). 6o H. Feichtinger, Chem. Eer. 104,1697(1971).

’’

Sec. III.C]

117

POLYCYCLIC ISOTHIAZOLES

(42)

(44)

(43)

(45)

(43).610-Cyanobenzenesulfonamides(44) are in equilibrium with 3-iminosaccharin (45), equilibrium being reached faster when R is an aryl group. Electron-donating groups in R push the equilibrium to the right.62 Workers in Japan described ways of making saccharin in high purity, free of toluenesulfonamide i r n p ~ r i t i e s . ~ ~

B. PHYSICAL PROPERTIES These were considered at length in the previous review.2A number of X-ray . crystallographic structures of saccharin salts have been reported.64

C. CHEMICAL PROPERTIES 3-Arylpseudosaccharinderivatives such as 46 are available from saccharin (41) by lithiation, followed by reaction with a halide6' or by reaction between saccharin and a Grignard reagent or an organolithium compound66;a further OR

R

L. A. Levy, J . Heterocycl. Chem. 8,873 (1971);Tetrahedron Lett., 3289 (1972). D. Balode, R. Valtere, and S. Valtere, Khim. Geterosikl. Soedin., 1632 (1978) [ C A 90, 120792 (1979)l. W. Koike,T. Kimoto,and S. Matsui,Ger. Offen. 2,616,61l(1977) [CA 86,171437(1977)];Jpn. Kokai 77/71,464 (1977) [CA 87, 168016 (1977)l. "N. Shimizu and S. Nishigaki, Acta Crystallogr., Sect. B B38, 1834 (1982);C39, 502 (1983). " A. L. Borror, L. Circotta, E. W. Ellis, J. W. Foley, and M. M. Kampe, US. Patent 4,181,660 (1980) [CA 92, 146747 (1980)l. 66 R. A. Abramovitch, E. M.Smith, M. Humber, B. Purtschert, P. C. Srinivasan, and G. M. Singer, J.C.S. Perkin I, 2589 (1974); P. C. Srinivasan, Ph. D. Thesis, University of Alabama (1975) [CA 85,192622 (1976)l. 62

118

[Sec. 1II.C

MICHAEL DAVIS

method is the heating of benzenesulfonamides that possess an aryl ketone moiety in the ortho position.67 Pseudosaccharin ethers (47; R = alkyl) also react with phenyllithium to give 3-phenylpseudosaccharin (46, R = Ph). However, the nucleophilic displacement reaction of 3-chloropseudosaccharin (48) remains the method of choice for preparation of substituted saccharins, and recent work includes improved procedures for preparing 48 and related compounds.68 Numerous examples have been given.69 T h e r m o l y s i ~of~saccharin ~ itself yields the benzoxazinone 49, which may be regarded as the dimer of the hypothetical imino ketene 50 produced by the elimination of sulfur dioxide from 41. Flash vacuum pyrolysis of 3arylpseudosaccharins (46; R = Ar) affords reasonable yields of 2-arylbenzoxazoles; 3-alkyl compounds (46; R = alkyl) yield aromatic nitriles only." 0

(49)

(fo)

Further examples of the formation of 3-aminopseudosaccharin derivatives (46; R = NHR', NR'R") from amines and saccharin have been reported."

Ring expansion reactions of saccharin have proved fertile areas of investigation. Two distinct types of reaction are involved (Scheme 1). In the first, ring expansion can occur by base-catalyzed ring opening at the carbonyl 0. 9. T. Nielsen, H. Brunn, C. Bretting, and C. W. Feit, J . Med. Chem. 18,41 (1975). K. Enoki, T. Fukui, T. Yamamoto, T. Okada, and H. Iwajo, Jpn. Kokai 77/36,663 (1977) [CA 87,152177(1977)]; M. Ito,T. Yamamoto, H.Iwashiro,T.Okada,and Y. Miyazaki, J p n . Kokai Tokkyo Koho 78 111,064 (1978) [CA 90,72172 (1979)l; P. C. Wade, B. R. Vogt, and T. P. Kissick, US. Patent 4,108,860(1978) [CA 90,87473 (1979)l;P. C. Wade and T. P. Kissick, US. Patent 4,104,388 (1978) [ C A 90, 72174 (1979)l; U.S. Patent 4,104,387 (1978) [ C A 90, 87441 (1979)l;P. C. Wade and B. R. Vogt, US. Patent 4,178,451 (1979) [CA 92, 110999 (1980)l. 6 9 A. Klemer, G. Uhlemann, S. Chahin, and M. N. Diab, Liebigs Ann. Chem., 1943 (1973); N. Matsumura, Y. Otsuji, and E. Imoto, Nippon Kagaku Kaishi, 1532 (1974) [CA 82, 4168 (1975)l; 1539 (1974) [ C A 82,57595 (1975)l;G . L. Bachman, J. W. Baker, and D. P. Roman, J . Pharm. Sci. 67, 1323 (1978). ' O A. J. Barker and R. K. Smalley, Tetrahedron Lett., 4629 (1971). '' R. A. Abramovitch and S. Wake, J.C.S. Chem. Commun., 673 (1977). 72 E. B. Pedersen and S . 0. Lawesson, Tetrahedron 30, 875 (1974); H. Kutlu, Istanbul Univ. Eczacilik Fak. Mecm. 11,254( 1975) [CA 87,68214 (1977)l;K . G. Jensen and E. B. Pedersen, Z. Naturjiorsch., B: Anorg. Chem., Org. Chem. 36B, 1640 (1981); Y. Imai, H. Okunoyama, K. Hirata, and M. Ueda, Nippon Kagaku Kaishi, 111 (1982) [ C A 96, 104134(1982)]. 67 68

Sec. III.C]

POLYCYCLIC ISOTHIAZOLES

(51)

/

119

EI (521: R ' = COzMe) (52b:R ' = H)

group, followed by a Dieckmann recyclization; this produces a 2H-1,2benzothiazine-4(3H)-one 1,l-dioxide (52; R = C0,Me).73 A similar product (52, R = H) is produced74 from 3-bromomethylpseudosaccharin (53, R = Br). Reaction of 3-methylpseudosaccharin (53, R' = H) with a dialkylaminoacetylene produces a benzothiazepine dioxide (54) in which the seven-memberedring is not aromatic. Thiadiazocinescan be produced from 3(2-hydroxyethylamino)pseudosaccharin (46; R = NHCH,CH,OH) by reaction with thionyl chloride.76The second type of reaction, with rupture of

''

73

J. D. Genzer and F. 0. Fontsere, US. Patent 3,960,856 (1976) [ C A 85,46728 (1976)l; A. C. Fabian, J. D. Genzer, C. F. Kasulanis, J. Shavel, and H. Zinnes, U.S. Patent 3,957,772 (1976) [CA 85, 46725 (1976)l; US. Patent 3,978,073 (1976) [CA 86, 16690 (1977)l; US. Patent 3,987,038 (1976) [CA 86, 72679 (1977)l; H. Zinnes, N. A. Lindo, and J. Shavel, U.S. Patent 4,074,048 (1978) [ C A 88, 190868 (1978)l; C. B. Schapira, I. A. Perillo, and S . Lamdam, J . Heterocycl. Chem. 17, 1281 (1980); I. A. Perillo, C. B. Schapira, and S. Lamdam, ibid. 20, 155 (1983); W. Herrmann, W. Geibel, and G. Satzinger, Ger. Offen. DE 3,212,485 (1983) [ C A 100,

22665 (1984)l. R.A. Abramovitch, K. M. More, I. Shinkai, and P. C . Srinivasan, J.C.S. Chem. Commun., 771 (1976). " R. A. Abramovitch, B. Mavunkel, and J. R. Stowers, J.C.S. Chem. Commun., 520 (1983). " J. Ashby, D. Griffiths, and D. Paton, J . Heterocycl. Chem. 15,1009 (1978). 74

120

MICHAEL DAVIS

[Sec. 1II.D

the S-N bond, is exemplified by the base-catalyzed ring expansion of the N-arylsaccharin 55 to the dibenzothiazepine dioxide 56.77

D. BIOLOGICAL PROPERTIES The long-standing controversy over the alleged human carcinogenicity of saccharin (41) intensified during the 1970s.In 1977 the United States Food and Drug Administration announced that, as a result of Canadian tests showing that the compound (at massive dosage levels) induced bladder cancer in rats, it intended to prohibit sale for human usage of saccharin. The proposed ban was deferred by the United States Congress. Two excellent and authoritative articles on the controversy are available. The first6 deals with the specific issue of saccharin, the second7' is concerned with the practicality of the 1958 Delaney clause, which in United States legislation requires the banning from food and beverages of any additive found carcinogenic in man or in animals. Neither saccharin nor any of the usual impurities present in commercial material is active in the Ames mutagenicity test.79 The metabolism of saccharin," of saccharin impurities,' and of other saccharin derivativesa2 has been studied. Claims have been made for the fungicidal activity of saccharin itselfa3 and of various halogeno derivative^,^^ for the diuretic action of 3-arylpseudosac3-(o-fluorophenyl)pseudosaccharinderivcharin ~ o r n p o u n d s ' ~ *including '~ a t i v e ~ for , ~ ~hypolipodemic activity of N-propionic and N-valeric acid derivatives," and for gastric acid inhibition by 3-aminopseudosaccharin D. Hellwinkel, R. Lenz, and F. Laemmerzahl, Tetrahedron 39,2073 (1983). Chem. Eng. News, 27 June, pp. 24-46 (1977). 79 J. Ashby, J. A. Styles, D. Anderson, and D. Paton, Food Cosmet. Toxicol. 16,95(1978) [ C A 89, 145167(1978)l. A. G. Renwick and R. T. Williams, Xenobiotica 8,475(1978). A. G.Renwick, Xenobiotica 8,487(1978). M. Uchiyama, H. Abe, R. Sato, M. Shimura, and T. Watanabe, Agric. Eiol. Chem. 37,737 Koeda, M. Odaki, T. Hisamatsu, H. Sasaki, M. Yokota, T.Niizato, S. Uchida, and T. (1973);T. Watanuki, Oyo Yakuri 13, 205 (1977)[ C A 88, 99161 (1978)l;R. Becker, E. Frankus, I. Graudums, W.A. Guenzler, F. C. Helm, and L. Flohe, Arzneim.-Forsch. 1101 (1982). 8 3 Y. Miyashiro, K. Fujishima, F. Araki,T. Hattori, and T. Okada, Jpn. Kokai 77/105,216(1977) [ C A 88,17320(1978)l. 84 I. Chiyomaru, E. Yoshinagu, and H. Ito, Jpn. Kokai 74/14,466(1974)[ C A 80,108506(1974)l; F. G . Bollinger and J. J. DAmico, US. Patent 4,006,007(1977)[ C A 87, 5948 (1977)l;J. Drabek, European Patent Appl. E P 86,748(1983)[ C A 99,175753(1983)l;R. J. Thiessen, US. Patent 4,410,353(1983)[ C A 100,34533(1984)l. " 0. B. T. Nielsen, C. K. Nielsen, and P. W. Feit, J . Med. Chem. 16,1170 (1973). 86 P. W.Feit, 0. B. T. Nielsen, and N. Rastrup-Andersen, J. Med. Chem. 16,127 (1973). 87 J. M. Chapman, G. H. Cocolas, and I. H. Hall, J. Med. Chem. 26,243(1983).

77

" W. Lijinsky, F. Coulston, S. M. Wolfe, and 1. G. Martin,

Sec. III.E]

121

POLYCYCLIC ISOTHIAZOLES

compounds.88N-Acylsaccharins are elastase inhibitors,*’ and the acetic acid derivative (57) is a potent sedative, hypnotic, and anticonvulsant comp~und.’~

@;CH(Et)CONH, so,

@ B r\ ;

(57)

so, (58)

(59)

N-Bromosaccharin (NBSac, 58) has been proposed as an alternative to Nbromosuccinimide; in some instances it gives better yields in benzyl brominati on^.^' 3-Substituted pseudosaccharin derivatives such as 59 may be used as condensing agents for peptide or ester ~ynthesis.’~The sodium salt of thiosaccharin (60)reacts with alkyl halides to give the 3-alkylthiopseudosaccharin (6l),an odorless, crystalline thiolequivalent.The thiol may be liberated by reaction with ~iperidine.’~

E.

RELATED

COMPOUNDS

Thiophenesaccharin(62) and its isomers (63and 64)are about twice as sweet as saccharin and lack any bitter afterta~te.’~ Reduced compounds, such as 33, have already been mentioned.*’ G. A. Schiehser and D. P. Strike, European Patent Appl. EP 81,955 (1983) [ C A 99, 158407 (1983)l. 89 D. Mulvey, H. Jones,and M. Zimmerman, Ger. Offen. 2,636,599 (1977) [ C A 87, 102315 ( 1977)l. 90 C. M. Svahn and N. A. Jonsson, Acta Chem. Scand., Ser. B B32,137 (1978). 9 ’ E. I. Sanchez and M. J. Fumarola, Synthesis, 736 (1976);J . Org. Chem. 47,1588 (1982). 92 A. Ahmed, H. Fukuda, K. Inomata, and H. Kotake, Chem. Lett., 1161 (1980); M. Ueda, N. Kawaharasaki, and Y. Imai, Synthesis, 933 (1982). 93 K. Inomata, H. Yamada, and H. Kotake, Chem. Lett., 1457 (1981); H. Yamada, H. Kinoshita, K. Inomata, and H. Kotake, Bull. Chem. SOC.Jpn. 56,949 (1983). 94 0.Hromatka and D. Binder, Ger. Offen. 2,534,689 (1976) [ C A 85,5612 (1976)l; P. A. Rossy, W. Hoffmann, and N. Mueller, J. Org. Chem. 45,617 (1980).

122

[Sec. 1V.A

MICHAEL DAVIS

IV. 2,1-Benzisothiazoles A. FORMATION

1 . From the Corresponding Benzisoxazole Reaction of 2,l -benzisoxazoles (65) with phosphorus pentasulfide affords the benzisothiazole 66.9s-97The yields are increased by the addition of imidazole or of 2-methylimidaz0Ie.~~

f$-pMse ‘N’

.N’

COMe

CO Me

2. By Hydrogen Peroxide Oxidation of 0-A mino thiobenzamides Further examples of the hydrogen peroxide oxidation of o-aminothiobenzamides have been reported.99 It is a reliable and reasonably versatile method, especially because the resulting 3-amino-2,1-benzisothiazoles can be diazotized and thus converted to a range of other 3-substituted compounds.’00 M. McKinnon and J. Y.Wong, Can. J. Chem. 49,2018(1971). 0.Aki, Y. Nakagawa, and K. Sirakawa, Chem. Pharm. Bull. 20,2372(1972). ” M. S . Chauhan and D. M. McKinnon, Can. J. Chem. 53, 1336 (1975). 98 0. Aki, K. Nakagawa, M. Yarnamoto, and K. Sirakawa, Japanese Patent 73/08,098(1973) [ C A 79,78779(1973)J 99 J. Norek, Barwniki-Srodki Pornocnicze 21,75(1977)[ C A 88,154310(1978)]; J. Gray and D. R. Waring, J. Heterocycl. Chem. 17,65(1980). loo M. Davis and K. S . L. Srivastava, Curr. Sci. 40,351 (1971); R.K. Buckley, M. Davis, and K. S. L. Srivastava, Aust. J . Chem. 24,2405(1971). ” D. 96

Sec. IV.A]

123

POLYCYCLIC ISOTHIAZOLES

(67)

(688: R = R' = H) (68b: R = CI, R' = H)

(69)

(a: R = R' = CI)

3 . From the Reaction of Thionyl Chloride or Related Compounds with o- Toluidines Onaka and Oikawa"' made an extensive study of the reaction between thionyl chloride and o-toluidine (67). They showed that, in addition to 42benzisothiazole and 5-chlorobenzisothiazole,'02 3-chloro- and 3,5-dichloro2,l-benzisothiazole were formed in considerable quantity. The reaction of o-ethylaniline with thionyl chloride affords, after workup, a good yield of 2,1-benzisothiazole-3-carboxylicacid (68, R = C02H, R' = H) together with the 5-chloro acid (68, R = CO,H, R' = Cl).'03,'04 3-Methyl-2,l-benzisothiazole, a presumed intermediate, is rapidly oxidized by thionyl chloride under the conditions of the reaction.lo3 Singerman'04s'05 made a significant advance in the usefulness of this reaction by replacing thionyl chloride with N-sulfinylmethanesulfonamide (69).Singerman's reagent (69)is easily obtained from methanesulfonamide and thionyl chloride. By use of this reagent, any aromatic or heteroaromatic compound containing adjacent methyl and amino groups may have a fused isothiazole ring grafted onto it. Better yields are usually obtained than by the thionyl chloride procedure, and chlorinated by-products are not formed.'06

4. From Other Nitrogen-Sulfur Transfer Reagents Thermolysis of N-thiosulfinyl-2,4-di-tert-butyl-6-methylaniline (70)affords reasonable yields of the 2,l-benzisothiazole (71). The same product is formed

lo'

Io4 lo'

Io6

T. Onaka and T. Oikawa, Itsuu Kenkyusho Nempo, 53 (1971) [ C A 77,48320 (1972)l. M. Davis and A. W. White, J.C.S. Chem. Commun., 1547 (1968); M. Davis, E. Homfeld, and T. G. Paproth, Org. Prep. Proced. f n t . 5,197 (1973). M. Davis, T. G. Paproth, and L. J. Stephens, J.C.S. Perkin I, 2057 (1973). G. M. Singerman, U.S. Patent 3,890,340 (1975). G. M. Singerman, J . Heterocycl. Chem. 12,877 (1975). G. M. Singerman, U.S. Patent 3,929,815 (1975);U.S. Patent 3,997,548 (1976).

1 24

[Sec. 1V.A

MICHAEL DAVIS

by irradiation of 70, followed by heating to reflux of a benzene solution of the intermediate sulfur diimide compound 72 (R = Ar) then formed.'" A similar intermediate (72, R = Ph) can be used in an unusual synthesis of 3cyano-2,1-benzisothiazole(73) in 67% yield from chlorocyanoketene (74).'OS

Me$

5 CI,

C=C=O

NC'

-

RN=S=NR

&S

Me&

+ 72 (R = Ph)

-

A related compound, the bis(trimethylsily1)sulfurdiimide (75) reacts with the lithiated silylamine 76 to afford a 70% yield of the benzisothiazole 77.'09

+ Me,SiN=S=NSiMe; M e q Me r L i ) S i (F)Me,

Me

5. Cycloaddition Reactions of Triphenylthien0[3,4-~]isothiazole Acetylenes add to the 1,3-dipolar system of triphenylthieno[3,4-~]isothiazole (78), giving an unstable bridged intermediate, which eliminates sulfur and forms the 2,l-benzisothiazole 79.' l o

lo'

lo*

lo9

llo

Y. Inagaki, R. Okazaki, and N. Inamoto, Tetrahedron Lett., 293 (1977). D. M. Goldfish, B. W. Axon, and H. W. Moore, Heterocycles 20,187 (1983). U. Klingebiel and D. Bentmann, Z . Naturforsch., B: Anorg. Chem., Org. Chem. 34B, 123 (1979); see also M. Davis, ibid. 35B,405 (1980). H. Gotthardt and F. Reiter, Tetrahedron Lett., 2163 (1976); Chem. Ber. 112,266 (1979).

Sec. IV.B]

125

POLYCYCLIC ISOTHIAZOLES

6 . Preparation of 2,l-Benzisothiazole 2-Oxides and 2,2-Dioxides Derivatives of 2,l -benzisothiazole 2-oxide (80) can be prepared by oxidation of o-aminophenylrnethylthiolmethane (81) with N-chlorosuccinimide and alkali, followed by further oxidation with rn-chloroperbenzoic acid."'

-

a

S

-

M

e r\ S

(81)

Ny C

oMe

(80)

The sulfonamide 82 is readily cyclized by potassium amide in liquid ammonia, affording I-methyl-2,l-benzisothiazoline2,2-dioxide (83).' '*-' l 4

Me

Me

B. PHYSICAL PROPERTIES The crystal and molecular structures of 5-chloro-2,l-benzisothiazole have been determined.ll5 The C-S and S-N bond distances are 1.664 and

"' T. E. Jackson, U.S.Patent 4,031,227(1977) [CA 87, 102318 (1977)l. J. F. Bunnett, T. Kato, R. R. Flynn, and J. A. Skorcz, J . Org. Chem. 28, l(1963).

'" J. A. Skorcz, J. T. Suh, and C. I. Judd, U.S.Patent 3,528,989 (1970) [CA 73, 130993 (1970)l. J. A. Skorcz, J. T. Suh, and C. I. Judd, U.S.Patent 3,560,512 (1971) [CA 74, 141766 (1971)l; J. A. Skorcz and J. T. Suh, J . Heterocycl. Chem. 9,219 (1972); J. A. Skorcz, J. T. Suh, and R. E. Germershausen, ibid. 10,249 (1973);11,73 (1974). '15'M. Davis, M. F. Mackay, and.W. A. Denne, J.C.S. Perkin 11,565 (1972).

'I4

126

MICHAEL DAVIS

[Sec. 1V.C

1.636 A, respectively, indicating significant double-bond characteristics in each; the C-S-N angle is 97.7", rather greater than in 1,2-benzisothiazoles. Proton'*26s'l 5 and "C-NMR' l 6 data have been reported for 2,l-benzisothiazole and substituted derivatives. Infrared and Raman assignments have been made for 2,1-ben~isothiazole,~~ and the electronic structure of this compound has been discussed.' l 7

C. CHEMICAL PROPERTIES 1. Diels-Alder Addition Reactions 2,1-Benzisothiazoles are not good Diels- Alder substrates; in early experiments only 3-alkylamino-2,1-benzisothiazoles(84) gave any evidence of reaction with maleic anhydride.' l a However, prolonged reaction (10 days, 90°C) of 2,l-benzisothiazole (68, R = R' = H) with acetylenedicarboxylate and propiolate esters produces substituted quinolines (85).'

(84) R = Me, Et

'

m

C

O N'

z -COzMe M e

2. Photochemistry and Thermolysis The photodecomposition of 2,l-benzisothiazoles removes the sulfur atoms. In methanol, o-aminoaryl aldehydes or o-aminoaryl ketones are formed,4°*120 'I6

11*

N. Plavac, 1. W. J. Still, M. S . Chauhan, and D. M. McKinnon, Can. J. Chem. 53,836 (1975). E. Chacko, J. Bornstein, and D. J. Sardella, J. Am. Chem. SOC.99,8248 (1977); M. H. Palmer and S. M. F. Kennedy, J . Mol. Struct. 43,33 (1978). M. Davis and K. S . L. Srivastava, J.C.S. Perkin I, 935 (1972). M. R. Bryce, R. M. Acheson, and A. J. Rees, Heterocycles 20,489 (1983). B. Jackson, H.Schmidt, and H.-J. Hansen, Helu. Chim. Acta 62,391 (1979).

Sec. IV.C]

POLYCYCLIC ISOTHIAZOLES

and in acetonitrile a dimer is produced:' proposed intermediates.'"

127

Thionitroso (N=S) compounds are

3, Decomposition of 2,1-Benzisothiazolium Quaternary Salts 2, I-Benzisothiazole and its derivatives readily form quaternary salts on treatment with alkyl or benzyl halides. These salts (86) are useful synthetic intermediates; the reactions they undergo are summarized in Scheme 2. The q u i n ~ l o n e s , ' ~benzodiazepi~~'~~ products include 2,1-ben~isothiazolines,~~ nones (including a one-step synthesis of the tranquilizer V a l i ~ m ) , ~ ~ * ' ~ ~ o-aminobenzaldehydesand o-aminoaryl ketone^,'^^^'^^ 2,l-benzisothiazole3 - t h i o n e ~ , and ' ~ ~ cyanine dyes,126the latter resulting from the activation of the methyl group in the 3-position of the quaternary salt (86, R = R' = Me). R = H, alkyl, aryl R' = alkyl, benzyl R 2 = H, CI, NO,

R' SCHEME 2

"' M. F. Joucla an lz4

C. W . Rees, J.C.S. Chem. Commun., 374 (1984). D. M. McKinnon, K. A. Duncan, and L. M. Millar, Can. J. Chem. 60,440 (1982). M. Davis and M. J. Hudson, J . Heterocycl. Chem. 20, 1707 (1983). K. Shirakawa, 0. Aki, K. Nagakawa, and M. Yamamoto, Japanese Patent 73/08,097 (1973) [ C A 79,92197 (1973)l. M. Davis, E. Homfeld, and K. S. L. Srivastava, J.C.S. Perkin I, 1863 (1973). N. F. Haley, J. Org. Chem. 43,1233 (1978).

128

MICHAEL DAVIS

[Sec. IV.D'

4. Reactions of 3-Chloro-2,l -benzisothiazole 3-Chloro-2,l-benzisothiazole(68, R = CI, R = H), which can be prepared from the 3-amino compound by a Sandmeyer reaction"' or from 2,lbenzisothiazolin-3(1H)-one by treatment with phosphoryl chloride,"' is similar to its 1,2 isomer (8)in that it is readily attacked by nitrogen, oxygen, sulfur, and carbon nucleophiles. This provides a good route to numerous 3O substituted 2,l -benzisothiazoles.

D.

2,1-BENZISOTHIAZOLIN-3( 1H)-ONE

1. Preparation of 2,l-Benzisothiazolin-3( IH)-ones Treatment of isatoic anhydride (87) with sodium hydrosulfide solution yieldsi2' the unstable thioanthranilic acid 88, which can be oxidized by 2,lhydrogen peroxide to 2,1-benzisothiazolin-3(lH)-one (89).127*131*132 Benzisothiazolin-3(1H)-thiones can be produced by the action of sodium sulfide on 2-aminobenzotrifluoride; the probable intermediate is the anion of di thioanthranilic acid.' 33

2. Reactions of 2,l-Benzisothiazolin-3(1H)-ones 2,1-Benzisothiazolin-3(lH)-oneand substituted derivatives exist predominantly in the keto form 89. Electrophilic substitution takes place readily, affording 5-substituted compounds. Like its 42 isomer, 89 is acidic and

If' 12*

''O

A. H. Albert, R. K. Robins, and D. E. OBrien, J. Heterocycl. Chem. 10,413 (1973). M. Davis, L. W. Deady, E.Homfeld, and S. P. Pogany, Aust. J . Chem. 28, 129 (1975). M. Davis, E. Homfeld, J. McVicars, and S. P. Pogany, Aust. J. Chem. 28,2051 (1975). A. H.Albert, D. E. OBrien, and R. K. Robins, J . Heterocycl. Chern. 15, 529 (1978). H. Boeshagen and W .Geiger, Chem. Ber. 106,376 (1973). J. Faust and R. Mayer, J. Prakt. Chem. 318,161 (1976). G. P. Jourdan and B. A. Dieikorn, J . Org. Chem. 47,5255 (1982).

'" "'

Sec. IV.E]

POLYCYCLIC ISOTHIAZOLES

129

dissolves readily in dilute base. Alkylation of the anion occurs exclusively at the nitrogen atom.’28 Treatment of 89 (R = H) with acetic anhydride and pyridine brings about sulfur elimination and a rapid rearrangement to produce the benzoxazinone (90, R = H, R’ = Me). A similar, slower reaction occurs with benzoyl chloride.’ 34 The latter reaction is autocatalytic, the “catalyst” being lowmolecular-weight sulfur produced by the elimination process.’ s Similar elimination reactions take place when 89 (R = H) is treated with isocyanate~.’ Triethyl phosphite will also bring about sulfur elimination from 89 (R = H), affording the bright yellow benzoxazinone (49); in pyridine solution pyracridone (91) is also formed. Remarkably, 91 can be produced simply by boiling a solution of 89 (R = H) in a mixture of pyridine and water.’37 The iminoketene 50 is apparently not an intermediate in these reactions.’ 3 6 ~ 317

E. APPLICATIONS Numerous azo dyes derived from 3-amino-2,1-benzisothiazole have been ~1aimed.l~’ The University of Parma group has continued to develop auxin analogues from derivatives of 2,1-benzisothiazole-3-carboxylic acid,’ 39 M. Davis and S. P. Pogany, J. Heterocycl. Chem. 14,267(1977). M. Davis and K. C. Tonkin, Aust. J. Chem. 34,755 (1981). 136 J. Perronet and L. Taliani, J . Heterocycl. Chem. 17,673(1980). 13’ M. Davis, R. J. Hook, and W. Y. Wu, J. Heterocycl. Chem. 21,369 (1984). 138 R. Niess, Ger. Offen. 2,412,975(1975)[ C A 84,46061(1976)l; R. J. Maner and M. A. Weaver, U.S.Patent 3,943,121(1976)[ C A 84,152215 (1976)l;G. Hansen, H. Kaack, and N. Grund, Ger. Offen. 2,507,460(1976)[ C A 86,157011 (1977)l;W. Deucker and R. Loewenfeld, Ger. Offen. 2,524,481 (1976)[ C A 86,91660 (1977)l;R. J. Maner and M. A. Weaver, U.S.Patent 4,070,352(1978)[ C A 88,154319 (1978)l;S. Imahori, Y. Murata, K. Abe, and S. Suzuki, Jpn. Kokai 78/65,480(1978)[CA 89,181173 (1978)l;H.Eilingsfeld, G. Hansen, G. Seybold, and G. Zeidler, Ger. Offen.’2,716,033(1978)[ C A 90, 73289 (1979)l;J. Dehnert and G. Lamm, Ger. Offen. DE 3,201,268(1983)[ C A 99, 177493 (1983)l. IJ9 E. Coghi, C. Branca, and G. Massimo, Ateneo Parmense, Acta Nat. 15,211 (1979)[CA 92, 158857 (1980)l;E. Coghi and C. Branca, ibid., 217 [ C A 93,2100 (1980)I. 134

135

130

MICHAEL DAVIS

[Sec. V.A

of 2,1-benzisothiazole-3-acetic acid,140 and from 3-acylamino-2,l-benzis~thiazoles.’~’Local anesthetic or antiinflammatory activity is shown and by by amides and esters of 2,1-benzisothiazole-3-carboxylic alkylaminoacetyl derivatives of 3-amino-2,l -benzis~thiazole.’~~ Azomethine derivatives of the latter compound have weak antifungal and antistaphylococcal activity. 144 An American company reports antiinflammatory activity in certain 3-(rn-substituted p-hydroxyphenyl) derivatives of 2,l-benzisothiaz01e.l~~ Some l-methyl-2,1-benzisothiazolin-3(1H)-one derivatives are claimed to have anticoagulant proper tie^.'^^ The 3-aminoalkyl derivatives of the 2,l-benzisothiazole 1,l-dioxides, developed by Skorcz and colleagues, have hypotensive and CNS-depressant activity.’ l 3

V. Other Isothiazole Systems Included among other isothiazoles are compounds closely related to benzisothiazoles: naphthoisothiazoles and systems with two or more isothiazole rings fused to a single benzene ring. Compounds which have a thiophene or pyridine ring, etc., fused to an isothiazole are omitted. A review of steroidal thiazoles, isothiazoles, thiazolines, and thiazolidines has appeared.’47

A. NAPHTHOISOTHIAZOLES Three of the four possible “angular” isomers of the naphthoisothiazole system (92,93,94) have been prepared by methods similar to those used in E. Coghi, C. Branca, G . Massimo, and F. Zani, Ateneo Parmense, Acta Nat. 16, 141 (1980) [CA 95,75268 (1981)l;A. Bellotti, C. Branca, E. Coghi, G. Massirno, and F. Zani, ibid. 18,25 (1982) [CA 97,67707 (1982)l. 14’ A. Bellotti, C. Branca, and E. Coghi, Ateneo Parmense, Acta Nat. 13,601 (1977)[CA 89,101651 (1978)l; 14,249 (1978) [ C A 90, 1572 (1979)l. L. Arnoretti, A. Bellotti, E. Coghi, and L. Zappia, Ateneo Parmeme, Acta Nat. 12,345 (1976) [CA 87, 62380 (1977)l; E. Coghi, G. Massimo, and L. Zappia, ibid. 15, 205 (1979) [ C A 92, 157721 (1980)J 143 A. Bellotti, E. Coghi, and L. Zappia, Ateneo Parmense, Acta Nat. 14,411 (1978) [CA 91,49567 (1 979)]. 144 A. Bellotti, E. Coghi, and 0. Sgorbati, Ateneo Parmense, Acta Not. 12, 123 (1976) [ C A 85, 187599 (1976)l. 14’ J. A. Carlson and M. R. Bell, US.Patent 4,122,105(1978) [ C A 90, 137801 (1979)l. 146 Kyowa Hakko Kogyo Co. Ltd., Jpn. Kokai Tokkyo Koho JP 82 108,016 (1982) [CA 97 133584 (1982)l. 14’ P. Catsoulacos and Ch. Camoutsis, J . Heterocycl. Chem. 18, 1485 (1981). I4O

Sec. V . B ]

131

POLYCYCLIC ISOTHIAZOLES

syntheses of 1,2-and 2,1-benzisothiazoles.17~14s~1so The "linear" isomer 95 has not yet been made. S-N

\

B.

\

'

BENZOBISISOTHIAZOLES AND BENZOTRIS[C] ISOTHIAZOLE

.nN

Meth-Cohn and co-workers have described the preparation of the benzobis[d]isothiazole 96 from the dialdehyde 97.'' O

H

Me,CS

C

aCHO SCMe,

i.HzNOH, ii. PPA

's

'

A particularly interesting reaction, capable of extension, is the addition of nitrile sulfides 98 to quinones. These nitrile sulfides are prepared by the thermolysis of 1,3,4-oxathiazo1-2-ones(W), and the products (with quinone itself) are the bis(isothiazo1o)benzoquinones All of the possible angular benzo[c]isothiazoles, of which 101 is one, and the symmetrical

M. Davis, G. C. Ramsay, and L. J. Stephens, Aust. J . Chem. 25, 1355 (1972). H. Adolphi, H. Fleig, and H. Hagen, Ger. Offen. 2,626,967 (1977) [CA 88, 136608 (1978)l; BASF A.-G., Belgian Patent 844,659 (1977) [ C A 88,17341 (1978)l. 150 J. Faust, J . Prakt. Chem. 319,65 (1977). R.M. Paton, J. F. Ross, and J. Crosby, J.C.S. Chem. Commun., 1194(1980). 148

spJysq

132

MICHAEL DAVIS

"'

[Sec. VI

'N'

5

(101)

(102)

benzotris[c]isothiazole 102 have been prepared by repeated use of Singerman's reagent.' s2

VI. Selenium and Tellurium Analogues A comprehensive review of selenium-nitrogen heterocycles has appeared.' s3 The selenium and tellurium analogues of 1,2-benzisothiazole can be prepared by procedures essentially similar to those used for 1,Zbenzisothiazole. Thus 1,2-benzisoselenazolin-3(2H)-one(103)may be prepared from the amide

_3

(104)

(!03)

104 by treatment with phosphorus pentachloride, followed by hydrolysis.' s4

1,2-Benzisotellurazole (105) can be prepared in 74% yield from the telluryl bromide 106'55;the selenium analogue is prepared similarly.1s6 An unusual

B. Danylec and M. Davis, J . Heterocycl. Chem. 17,533 (1980). I. Lalezari and A. Shafiee, Adv. Heterocycl. Chem. 24,109 (1979). w R. Weber and M. Renson, J . Heterocycl. Chem. 10,267 (1973); Bull. SOC.Chim. Fr., 1124 (1976); Bull. SOC.R . Sci. Liege 48,146 (1979). 15' R. Weber, J. L. Piette, and M. Renson, J . Heterocycl. Chem. 15,865 (1978). D. E. Ames, A. G. Singh, and W. F. Smyth, Tetrahedron 39,831 (1983).

Sec. VI]

POLYCYCLIC ISOTHIAZOLES

133

preparation of a 1,2-benzisoselenazole (107) is that achieved by treatment of 2,1,3-benzoselenadiazole (108) with benzyne.’” Naphtho[2,3-c][1,2,5]selenadiazole undergoes a similar reaction, affording 3-substituted benzisoselenazoles in low yields.lS8 CH=CH-CH=CH-CN

(W

(107)

The crystal and molecular structures of 105 have been determined; it has an anomalous structure with very short intermolecular Te-N bonds of 2.4 a.1s9 Mass spectral,” ‘jC- and ”Se-NMR data’60 of 1,2-benzisoselenazoles have been reported. The intramolecular Se-N bond in these compounds is weaker than in 1,2-benzisothiazolesand is readily cleaved by organolithium reagents.’ 6 1 ~ 1 62

Is’

C. D. Campbell, C. W. Rees, M. R. Bryce, M. D. Cooke, P. Hanson, and J. M. Vernon, J.C.S. Perkin I, 1006 (1978); M. R. Bryce, C. D. Reynolds, P. Hanson, and J. M. Vernon, ibid., 607 (1981).

J. M. Vernon, M. R. Bryce, and T. A. Dransfield, Tetrahedron 39,835 (1983). H. Campsteyn, L. Dupont, J. Lamotte-Brasseur, and M. Vermeire, J. Heterocycl. Chem. 15, 745 (1978). “O

N. V. Onyamboko, M. Renson, S.Chapelle, and P. Granger, Org. Magn. Reson. 19,74 (1982). R. Weber and M. Renson, J . Heterocycl. Chem. 12, 1091 (1975). N. V. Onyamboko, R. Weber, A. Fauconnier, and M. Renson, Bull. Soc. Chim. Belg. 92, 53 (1983).

This Page Intentionally Left Blank

ADVANCES IN HETEROCYCLIC CHEMISTRY. VOL. 38

1.4.Benzothiazines. Dihydro.l.4.benzothiazines. and Related Compounds C. BROWN AND R. M . DAVIDSON The Chemical Laboratory. University of Kent at Canterbury. Canterbury. Kent. England

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 135 138 I1. Natural Occurrence . . . . . . . . . . . . . . . . . . . . . . . 111. Pharmacology of 1.4.Benzothiazinesand Their Derivatives . . . . . . . . . 142 A. Antiinflammatory and Antihistaminic Activity . . . . . . . . . . . . 143 144 B. Ataractic Activity . . . . . . . . . . . . . . . . . . . . . . C. Miscellaneous Applications . . . . . . . . . . . . . . . . . . . 145 145 IV. Agricultural Uses . . . . . . . . . . . . . . . . . . . . . . . . V. IndustrialUses . . . . . . . . . . . . . . . . . . . . . . . . 146 146 VI. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . A. Preparation from 2-Aminobenzenethiols . . . . . . . . . . . . . . 146 1. Reaction with Unsaturated Carbon-Carbon Bonds . . . . . . . . . 146 2. Reactions with Epoxides . . . . . . . . . . . . . . . . . . . 147 3. Reaction with a-Halo Acids and a-Halo Esters . . . . . . . . . . . 148 4. Reaction with a-Halo Ketones and Derivatives . . . . . . . . . . . 149 5 . Reactions with 1,3-Diketones and /?-Keto Esters . . . . . . . . . . . 150 6. Reaction with Other Compounds . . . . . . . . . . . . . . . . 151 B. Preparation by Ring Expansion . . . . . . . . . . . . . . . . . 154 C. Preparation from 2-Nitrobenzenethiols . . . . . . . . . . . . . . . 159 1. Reaction with Unsaturated Carbon-Carbon Bonds . . . . . . . . . 159 2. Reaction with a-Halo Acids and Esters . . . . . . . . . . . . . . 159 160 3. Reaction with Halides . . . . . . . . . . . . . . . . . . . . 4. Other Reactions with the SH Group . . . . . . . . . . . . . . . 161 D. Preparation from 2-Nitrobenzenesulfenyl Chlorides . . . . . . . . . . 161 E. Preparation from Disulfides, Cysteine Derivatives, and Other Reagents . . . . 163 F. OtherRoutes . . . . . . . . . . . . . . . . . . . . . . . . 165 VII. Reactions of 1,4-Benzothiazines. . . . . . . . . . . . . . . . . . . 167 A. N-Alkylation and N-Acylation . . . . . . . . . . . . . . . . . . 167 B. Electrophilic Substitution . . . . . . . . . . . . . . . . . . . 169 C . Nucleophilic Substitution . . . . . . . . . . . . . . . . . . . 171 D. Rearrangement Reactions . . . . . . . . . . . . . . . . . . . 172 E . Oxidative Coupling of 1,4-Benzothiazines . . . . . . . . . . . . . . 175

.

I Introduction The benzothiazines constitute a group of heterocyclic compounds which are especially interesting owing to their occurrence in nature as mammalian 135

Copyright 0 1985 by Academic Press. Inc. All rights of reproduction in any form reserved. ISBN 0-12-020638-2

136

[Sec. I

C. BROWN AND R. M. DAVIDSON

pigments and to their extensive pharmacological activity. In addition, they have found a variety of industrial uses and show promise as herbicides. Possible isomeric ring structures for this class of compounds are given in formulas 1-9. H

IH-2,l

4H- 1,2 (5)

2H-3,l

4H-1,3 (6)

4H-3.1

2H- 1,2

2H-1.3

2H- 1,4

4H- 1,4

(7)

(8)

(9)

The chemistry of 1,3-benzothiazines has been reviewed as have the 42- and 2,l -benzothiazines and benzothiazinone dioxides. The 1,Cbenzothiazines have not been reviewed comprehensively, however, although a number of articles are available containing shorter resumes of their This review, which covers the period through mid-1981, including Chemical

’-’

’ J. Szabo, Khirn. Geterosikl. Soedin., 291 (1979) [CA 91, 39354 (19791. P. Catsoulacos and C. Camoutsis, J . Heterocycl. Chem. 16, 1503 (1979). ’J. G. Lombardino and D. E. Kuhla, Adu. Heterocycl. Chem. 28,73 (1981). M. Salisbury, in “Road‘s Chemistry of Carbon Compounds” (S. Coffey,ed.), 2nd ed., Vol. IVH, p. 509. Elsevier, Amsterdam, 1978. G. Prota, I n “Organic Chemistry of Sulphur, Selenium and Tellurium” (Specialist Periodical Reports), Vol. 1, p. 454. Chemical Society, London, 1970. G. Prota, I n “Organic Chemistry of Sulphur, Selenium and Tellurium” (Specialist Periodical Reports), Vol. 2, p. 758. Chemical Society, London, 1973. G. Prota, I n “Organic Chemistry of Sulphur, Selenium and Tellurium” (Specialist Periodical Reports), Vol. 3, p. 708. Chemical Society, London, 1975. * G. Prota, I n “Organic Chemistry of Sulphur, Selenium and Tellurium” (Specialist Periodical Reports), Vol. 4, p. 453. Chemical Society, London, 1977. J. Piechaczek, W a d . Chem. 20,233 (1966) [CA 65,3864 (1966)J

’

’

Sec. I]

1,4- AND DIHYDRO- 1,CBENZOTHIAZINES

137

Abstracts, Vol. 94, is primarily concerned with 2H- and 4H-1,4benzothiazines, (8 and 9), and their dihydro derivatives, though some references will be made to 1,Cbenzothiazine 1,l-dioxides and 1,4benzothiazin-3-ones, since these compounds have a common ring skeleton together with, in certain cases, comparatively similar chemical behavior. To date, the unstable parent ring of the 1,4-isomers (8 and 9) has not been isolated, although it has been observed by 'H NMR as a transient species existing only in solution, predominantly as the 2H tautomer." The first synthesis of a derivative was reported by Unger," who claimed that reaction of phenacyl bromide with 2-aminobenzenethiol gave 3-phenyl2H-l,4-benzothiazine (loa).Nearly 70 years later Friedrich et al. proposed the 4H structure (lob).

''

After reexamination of the reaction product, using UV and 'H NMR, two groups claimed that it was a mixture of the 2H (80%) and 4H (20%) t a ~ t o r n e r s . " * However, ~~ more recently, Thomson et al. have shown that these results are also rather a m b i g u ~ u s . 'Thus ~ the 4'-methoxy and 4'-nitro derivatives of 10 could be obtained as monomers only by using a rapid workup procedure. The procedure of Unger and a later one described by Finar and Montgomery'6 both give only the dimer (11). Ar = 4-CH30C,H, Ar = 4-N02C6H,

F. Chioccara,G. Prota, and R. H.Thomson, Tetrahedron 32,1407 (1976). 0.Unger, Ber. Dtsch. Chem. Ges. 30,607 (1897). W. Friedrich, F. Krohnke, and P. Schiller, Chem. Ber. 98,3804 (1965). I 3 P. Bottex, B. Sillion, G. de Gaudemaris, and J.-J. Basselier, C. R. Hebd. Acad. Sci., Seances Ser. C 267, 186 (1968). M. Wilhelm and P. Schmidt, J . Heterocycl. Chem. 6,635 (1969). I' N. E. MacKenzie, R. H. Thomson, and C. W. Greenhalgh,J.C.S. Perkin I , 2923 (1980). l 6 I. L. Finar and A. J. Montgomery, J . Chem. Soc., 367 (1961).

138

C. BROWN AND R. M. DAVIDSON

[Sec. I1

X-Ray studies of the system, using dimethyl 4-formyl-2,3-dihydro-1,4benzothia~ine-2,3-dicarboxylate,~~ 4H-1,4-benzothiazine 1,l-dioxide,’* and the 3-methyl deri~ative,’~ showed these molecules to be essentially planar with only small distortions associated mainly with the heteroatoms in the thiazine ring. The various bond lengths and angles were related to those of indole in an attempt to rationalize their reactivity toward electrophiles, which has been reportedZo to be similar to that of indole. Molecular mechanics calculations similarly indicated essentially planar rings for trans-2-dimethyl-4acetyldih ydrobenzothiazine. I Mass spectral fragmentation patterns of dihydro-1,4-benzothiazinehave been studied and dissociation mechanisms discussed.22 The neutral 1,4benzothiazinyl radical 12 has recently been reportedZ3 and compared with phenothiazinyl

(12)

The acidity of the NH group has been examinedZ7in a range of heterocycles including 1,Cbenzothiazines. As the heterocyclic ring becomes smaller, the NH acidity increases, and therefore the nitrogen center becomes less reactive with respect to electrophiles. Thus change in the pK is enhanced when sulfur and nitrogen are present in the ring.

11. Natural Occurrence The 1,Cbenzothiazine ring is the basic unit for the phaeomelanins and trichochrome melanin pigments found in mammals, particularly in red hair H. Ogura, K. Kikuchi, H.Takayanagi, K. Furuhata, Y. Iitaka, and R. M. Acheson, J.C.S. Perkin I, 2316 (1975). G . D. Andreetti, G. Bocelli, and P. Sgarabotto, Cryst. Struct. Commun. 3,305 (1974). l 9 G . D. Andreeti, G. Bocelli, L. Coghi, and P. Sgarabotto, Cryst. Struct. Commun. 5,315 (1976). 2o G. Pagani and S . 9. Pagani, Tetrahedron Lett., 1041 (1968). 2 1 R. M. Davidson, Ph. D. Thesis, University of Kent (1981). 22 H. Budzikiewicz and U. Lenz, Org. Mass Spectrom. 10,992 (1975). 23 F. Ciminale, G. Liso, and G. Trapani, Tetrahedron Lett. 22, 1455 (1981). 24 M. F. Chiu, 9. C. Gilbert, and P. Hanson, J . Chem. SOC.B, 1700 (1970). ” Y.Tsujino, Tetrahedron Lett., 41 1 (1968). 2 6 C. Jackson and N. K. D. Patel, Tetrahedron Lett., 2255 (1967). M. V.Gorelik, T. V. Levandovskaya, B. A. Korolev, M. I. Terekhova, E. S. Petrov, and A. I. Shatenshtein, J . Org. Chem. USSR (Engl. 7kansl.) 14,2202 (1978) [CA 90, 10366 (1979)l.

’’

Sec. 111

1,4-AND DIHYDRO-1,CBENZOTHIAZINES

139

and feathers. The occurrence and biogenesis of pigments have been rev i e ~ e d , ’ ~and - ~ ~so only a resume will be given. Phaeomelanins are reddish-brown, nitrogen and sulfur-containing macromolecular pigments, which are found in phaeomelanocytes. They are derived from tyrosinase oxidation of tyrosine and subsequent reaction with cysteine. Trichochromes are produced in a similar manner, but they are of low molecular weight and usually yellow, red, or violet. The commonly encountered trichochromes have the structures 13 and 14.

(13)Trichochrome B, R = H, R’= CH,CH(NH,)CO,H (14) Trichochrome C, R = CH,CH(NH,)CO,H, R‘ = H

OH

OH

E,R = H, R’= CH,CH(NH,)CO,H (16)Trichochrome F, R = CH,CH(NH,)CO,H, R‘ = H (15) Trichochrome

Trichochromes E and F are based on the 2H-1,4-benzothiazine ring, while trichochromes B and C are mixed systems, with both 1,4-benzothiazine and 1,4-benzothiazin-3-one fragments. These may be extracted from red hair and feathers under alkaline condition^.^'.^^ Apparently33 only trichochromes B and C occur in red feathers, and trichochromes E and F, reportedly isolated from this source, arise as artifacts. The chromophore in the trichochrome G. Prota and R. H. Thomson, Endeavour 35,32(1976). R.H. Thomson, Angew. Chem., lnt. Ed. Engl. 13,305(1974). 30 G. Prota, in “Pigmentation: Genesis and Biological Control” (V. Riley, ed.), p. 615.Appleton, New York, 1972. 31 R. A. Nicolaus, G. Prota, C. Santacroce, G. Scherillo, and D. Sica, Gazz. Chim ltal. 99, 323 ( 1969). ” G. Prota, A. Suarato, and R. A. Nicolaus, Experientia 27,1381 (1971). 3 3 G. Agrup, C. Hansson, H. Rorsman, A-M. Rosengren, and E. Rosengren, Acta Derm. Venereol. 58,269(1978)[CA 90,36495(1979)l. 29

140

[Sec. I1

C. BROWN AND R. M. DAVIDSON

system is analagous to that of indigo. Consequently, many recent studies have been aimed at reproducing the chromophore system 17 synthetically. -S \

cis-(l7)

trans-(17)

(18)

Prota and c o - ~ o r k e r prepared s~~ 18 by oxidative coupling of 3-aryl-2H1,4-benzothiazines,and established the structures of the cis and trans isomers of the 3-p-bromophenyl derivatives by X-ray crystallography. The cis and trans isomers are readily interconverted in solution at room temperature, with the red, cis isomer predominating over the yellow, trans isomer, both isomers being stable in the solid state. The dominance of the cis isomer can be attributed to Van der Waals forces, which maintain the two benzene rings at the 3,3’-positions in an almost fixed conformation. In the trans isomer, the benzene rings are relatively free. As the temperature is increased, thermal motion destabilizes the cis configuration and the less strained trans isomer becomes favored. Kaul synthesized the chromophore based on 1,4-benzothiazin-3-one to obtain the skeleton 19 for trichochromes B and C.3s

(19)

Prota’s method cannot be employed in the synthesis of the trichochrome E and F skeleton because it would require the unstable 2H-lP-benzothiazine 8 as starting material. However, the Italian group observed the spontaneous formation of compound 20 while attempting to prepare 2H- 44-benzothiazine 34 35

F. Giordano,L. Mazzarella, G .Prota, C. Santacroce,and D. Sica, J . Chem. Sec. C, 2610 (1971). B. L. Kaul, Helu. China. Acta 57,2664 (1974).

Sec. 111

1,4- AND

141

DIHYDRO-1,4-BENZOTHIAZINES

(8)and developed from this a simple method for the preparation of 20 in good yield.

’

Under anaerobic conditions, the trimer 21 was formed, presumably by an aldol rea~tion.~’ Treatment with hydrochloric acid in ethanol exposed to the air gave the dimer. This had led to the suggestion that under aerobic conditions, the trimer is converted to phaeomelanic pigments, which may be formed by aldol-type condensation and not by oxidative coupling as previously proposed.’ As mentioned, the amino acid cysteine is thought to be involved in the biosynthesis of trichochromes. Cysteine reacts with 4-methyl-Obenzoquinone to give 22, which on treatment with mineral acid gives the trichochrome chromophore systern,4’ and reactions of cysteine ethyl ester and of 2-aminoethanethiol with quinones were studied to elucidate and duplicate the natural ~ y n t h e s i s . ~ ” ~ ~

C02H 0

OH

G . Prota, E. Ponsiglione,and R. Ruggiero, Tetrahedron 30,2781 (1974). F. Chioccara,E. Novellino, G. Prota, and G . Sodano, J.C.S. Chem. Commun., 50 (1977). G . Prota, G. Scherillo, E. Petrillo, and R. A. Nicolaus, Gazz. Chim. Ital. 99,1193 (1969). 39 D. Sica, C. Santacroce, and G. Prota, J. Heterocycl. Chem. 7,1143 (1970). 40 S. Crescenzi, G. Misuraca, E. Novellino, and G. Prota, Chim. Ind. (Milan) 57,392 (1975). 41 G. Prota and E. Ponsiglione, Tetrahedron Lett., 1327 (1972). 42 G. Prota, 0.Petrillo, C. Santacroce,and D. Sica, J. Heterocycl. Chem. 7,555 (1970). *’ G. Prota, G. Scherillo, E. Napolano, and R. A. Nicolaus, Garz. Chim. Ital. 97,1451 (1967). J6

37

142

C. BROWN AND R. M. DAVIDSON

[Sec. I11

The biosynthesis of luciferin (23)in the luminescent click beetle, Pyrophorus pellucens, is proposed to occur via the reaction of quinone with cysteine to give an intermediate benzothiazine, which on further reaction with cysteine gives the benzothiazole. But preliminary studies with 14C-labeled cysteine indicated, however, that an alternative fate for the first-formed thiazine, involving oxidation and ring contraction, may have to be ~ o n s i d e r e d . ~ ~ 0

0

(23)

Rifamycin Verde from mutant strains of Nocardia mediterranea contains the 1,4-benzothiazine skeleton, the formation of which is proposed from cysteine of cysteamine derivatives and Rifamycin S.45*46

111. Pharmacology of 1,4Benzothiazines and Their Derivatives Much interest in the pharmacology of 1,Cbenzothiazines is due to their similarity in structure with phenothiazine drugs, such as chlorpromazine (24),

CH,CH,CH,NMe,

44

F. McCapra and Z. Razavi J.C.S. Chem. Commun., 153 (1976).

P. Antonini, G. C. Lancini, G. Tamborini, R. J. White and E. Martinelli, Tetrahedron 36,1415 (1980). 46 R. Cricchio, Tetrahedron 36,2009 (1980). " R. Cricchio,

Sec. III.A]

1,4- AND DIHYDRO-l,4-BENZOTHIAZINES

143

which are widely used in many areas of medicine. The synthesis of phenothiazine drugs has been reviewed along with their c h e m i ~ t r y . ~ ’1,4*~~ Benzothiazine derivatives display pharmacological activity in a number of areas, which are considered in the sections below.

A. ANTIINFLAMMATORY AND ANTIHISTAMINIC ACTIVITY Substituted 1 ,Cbenzothiazines were first reported to exhibit antihistaminic properties by 4-(DimethylaminoethyI)-6-chloro-3,4-dihydro-1,4benzothiazine (25) is particularly active.49

I

CH,CH,NMe2

(25)

Further studies produced active compounds 26 with a carbonyl function in the side chain, and these display antifungal activity in addition to antiinflammatory proper tie^.^' Winthrop prepared compounds 27, which display

u:l

X

I

a:a” I

X = halogen or alkyl; R = alkyl

antihistaminic and spasmolytic activity.” The benzothiazines 28 also exhibit antiinflammatory proper tie^.^^.^^ D. Lednicer and L. A. Mitscher, “Organic Chemistry of Drug Synthesis,” p. 372.Wiley, New York, 1977. 48 C. Bodea and 1. Silberg, Adu. Heterocycl. Chem. 9,321(1968). 49 K. Fujii, Japanese Patent 5241 (1958)[ C A 53,17156(1959)l. ” H. S . Lowrie, U.S.Patent 2,947,744(1960)[ C A 55,583(1961)J S. 0.Winthrop and R. Gaudry, U.S. Patent 2,989,528(1961)[ C A 56,4777(1962)l. ” J. Krapcho and C. E. Turk, J . Med. Chem. 16,776(1973). ” R. C. Millonig, M. B. Goldlust, W. E. Maguire, B. Rubin, E. Schulze, R. J. Wojnar, A. R. Turkheimer, W. F. Schreiber, and R. J. Brittain, J. Med. Chem. 16,780 (1973). 47

’’

144

[Sec. 1II.B

C. BROWN AND R. M. DAVIDSON

(28)

R

=

CH(0H)Me; COMe

B. ATARACTIC ACTIVITY 1,4-Benzothiazines find extensive use as ataractic agents, i.e., tranquilizers and central nervous system (CNS) depressants. 4(Hydroxyalkylcyclicamino)propyl-2-phenyl-3,4-dihydro1,4-benzothiazines (29) show CNS depressant without including the anorexia associated with the use of related 1,4-benzothiazine derivative^^^.^^ such as 30.

ayph ,yph I

I

n

CHz(CHz)zN\__/N(CHz)zOH

(29)

CO(CH,),NMe,

(30)

Krapcho” found the acid salts of N-aminoalkylbenzothiazinederivatives (31) to have ataractic and antispasmodic properties, and to be particularly

useful in the treatment of parkinsonism. Substituted 2-phenyl-1,4benzothiazin-3-ones can antagonize the activity of 1,4-dipyrrolidine-2butyne, which induces tremors and is used as a guide to evaluate compounds

R = alkyl, aryl; R = H, alkyl, hydroxyalkyl H. S. Lowrie, U.S. Patent 3,124,577 (1964) [ C A 60, 14515 (1964)J J. Krapcho, U.S. Patent 3,143,545 (1964) [ C A 61,9507 (1964)l. 5 6 J. Krapcho, U.S. Patent 3,089,872 (1963) [ C A 59, 11541 (1963)l. 5 7 J. Krapcho and H. L. Yale, U.S. Patent 3,117,124 (1964) [ C A 60, 8048 (1964)l.

54

55

Sec. IV]

1,4- AND DIHYDRO-1,4-BENZOTHIAZINES

145

in the treatment of parkin~onism.’~ Other derivatives display CNS depressant activity and, in some cases, antibacterial activity.” CNS depressant, antispasmodic, and antiulcer activities are exhibited6’ by 2-alkylcyclicaminoacetyl derivatives 32.

C. MISCELLANEOUS APPLICATIONS Various derivatives are also active as ant helm in tic^,^'-^^ muscle relaxa n t ~ , ’ . diureti~s,~’ ~~ antimycotics,66 antihypertensive^,^' and anticholesterics.68 The metabolism of 4-[3-dimethylaminopropyl]-3,4-dihydro-2-( 1hydroxyethyl)-3-phenyl-2H- 1,Cbenzothiazine in uiuo by rats, dogs, and monkeys has been studied, and at least five metabolites were isolated.69

IV. Agricultural Uses The plant physiological activity of 1,Cbenzothiazines has been little studied. Worley reports that compounds 33 destroy or prevent growth of some broad-leaved weeds, yet promote the growth of some dicotyledonous

I

CH ,CO,R (33) R = H, alkyl R’, R 2 = H, alkyl, alkylidene, aryl ” J.

X

H

(34)X = halogen

Krapcho, A. Szabo, and J. Williams, J. Med. Chem. 6,214 (1963). Krapcho, U.S. Patent 3,401,166 (1968) [ C A 69, 106721 (1968)l. 6o J. F. Cavalla and J. Michael, British Patent 1,244,481 (1971) [ C A 75, 129824 (1971)l. 61 A. Mackie and J. Raeburn, J . Chem. Soc., 787 (1952). 6 2 A. Mackie, G. M. Stewart, A. A. Cutler, and A. L. Misra, Br. J . Pharmacol. Chemother. 10, 7 (1955). 6 3 A. Mackie and G. M. Stewart, Arch. Int. Pharmacodyn. Ther. 102,476 (1955). 64 W. K. Hoya, U S . Patent 3,148,188 (1964) [ C A 61, 13324(1964)]. ” H. Kano, S. Takahashi, Y.Ogawa, T. Yoshizaki, and T. Kitakaze, Shionogi Kenkyusho Nempo 11, 1 (1961) [ C A 56,4749 (1962)l. 66 H.Boshagen and M. Plempel, U.S. Patent 3,911,126 (1975) [ C A 84, 155700 (1976)l. “ R. N. Prasad, J. Med. Chem. 12,290 (1969). 6 8 K. Irmscher, J. Kraemer, G. Cimbollek, D. Orth, H. Novwack, and K. 0.Freisberg, Ger. Ofen. 1,809,454 (1970) [ C A 73,66594 (1970)l. 69 S. J. Lan, T. J. Chando, A. I. Cohen, I. Weliky, and E.C. Schreiber, Drug Metab. Dispos. 1,619 (1973). ” J.

146

C. BROWN AND R. M. DAVIDSON

[Sec. V 1 . A

crops such as legumes.70Compounds 34display herbicidal activity, but do not damage main crops and show low toxicity to fish and mammals.71

V. Industrial Uses 1,4-Benzothiazines have been used in industry as dyes and as antioxidants of rubber and natural elastomers. They have been used widely to prepare azodye compounds with specific properties, such as water insolubility, which is useful in the dyeing of polypropylene fibers, and increased stability to gas Several reports are concerned with the antioxidant properties of b e n z ~ t h i a z i n e s , ~and ~ - ~their ~ use as color photography developer^.^^

VI. Synthesis A . PREPARATION FROM 2-AMINOBENZENETHIOLS

2-Aminobenzenethiol is the most commonly used starting material, reacting with a large variety of functional groups to give substituted 1,4benzothiazines.

1 . Reaction with Unsaturated Carbon-Carbon Bonds 2-Aminobenzenethiol reacts with acetylenes and olefins to give 1,4benzothiazines. Reaction with acetylene dicarboxylic acid and esters gives the 2-alkylidene derivates (35).79*80 J. W. Worley, US.Patent 3,923,709 (1975) [ C A 84, 74279 (1976)l. Yematsu, S. Hashimoto, and H. Oshio, British Patent 2,018,754 (1979) [CA 93, 46693 (1980)J 7 2 R. Tanaka, K. Teramura, and S. Yokoyama, Japanese Patent 41/5833 (1966) [CA 65, 9062 (1966)J ’3 J. B. Dickey, W. H. Strain, and R. A. Corbitt, U.S.Patent 2,364,347 (1944) [ C A 39, 4233 (19491. 74 J. B. Dickey and J. G . McNally, U.S. Patent 2,374,181 (1945) [CA 40, 1180(1946)]. 7 5 L. Convert and R. Fabre, French Patent 1,344,437 (1963) [CA 61, 5885 (1964)l. 76 Rhone-Poulenc S. A., French Patent 84,357 (1965) [CA 62, 14914(1965)]. 77 I. Ya Postovskii, U.S.S.R.Patent 707,915 (1980) [ C A 92, 148252 (1980)l. W. H. Strain and J. B. Dickey, U.S.Patent 2,381,935 (1945) [CA 40,1889 (1964)J 79 L. K. Mushkalo and V. A. Besemskaiya, Ukr. Khim. Zh. 18,163 (1952) [CA 48,13692 (1953)l. Y. Maki and M. Suzuki, Chem. Pharm. Bull. 20,832 (1972). 70

” T.

Sec. VI.A]

1,4- AND DIHYDRO- 1,CBENZOTHIAZINES

147

(35)

Similar reactions occur with a,S-unsaturated acids," though earlier literature had suggested that 1,5-benzothiazepines (36) were produced.82

2. Reactions with Epoxides One synthesis of benzothiazines via a-epoxy ketoness3 involves acidcatalyzed ring expansion of a benzothiazoline intermediate (37) to give the benzothiazine derivative 38.

F. K. Kirchner and E. J. Alexander, J . Am. Chem. SOC.81, 1721 (1959). W. H. Mills and J. B. Whitworth, J . Chem. Soe., 2738 (1927). 8 3 L. G. Gobalenko, L. K. Mushkalo, and V. A. Chiuguk, Ukr. Khim. Zh. 35,1278 (1969) [ C A 72, 78963 (1970)l.

8z

148

C. BROWN AND R. M. DAVJDSON

[Sec. V1.A

Early reports that 2-substituted dihydro-1,4-benzothiazines(39) could be prepared from 2-aminobenzenethiol with e p o x i d e ~ ~ were ~ * ~ ’later shown incorrect.86-88 The actual product is the amino alcohol 40. Fujii” claimed, however, that heating the hydrochloride salt of 40 (R = H) did produce 3,4dihydro-1,4-benzothiazine(39, R = H), and more recently it has been shown that benzothiazines can be obtained by reaction of perfluoroepoxides with 2aminoben~enethiol.~~

3. Reaction with a-Halo Acids and a-Halo Esters Funke

et

al. used a-bromophenylacetic acid to prepare 2-phenyl-3,4-

dihydro-1,4-benzothiazine(41) via a lithium aluminum hydride reduction of the 1,4-benzothiazin-3-one intermediate.” Similarly, chloroacetic acid gives products not substituted in the 2-po~ition.~’

(41)

a-Halo-P-carbonyl esters give 4H-1,4-benzothiazines (42) with anhydrous The chlorine diethyl ether or aqueous potassium hydroxide/methan~l.~~*~~

C. C. J. Culvenor. W. Davies, and N. S. Heath, J. Chem. Soc., 278 (1949). R. Fusco and G. Palazzo, Gazz. Chim. Ital. 81,735 (1951). 86 J. F. Kerwin, J. E. McCarty, and C. A. VanderWerf, J . Org. Chem. 24, 1719 (1959). 87 0. Hromatka, J. Augl, A. Brazda, and W. Griinsteidl, Monatsh. Chem. 90,544 (1959). K. Fujii, Yukugaku Zasshi 77,355 (1957) [ C A 51, 12012 (1957)l. 89 N. Ishikawa and S . Sasaki, Bull. Chem. SOC.Jpn 50,2164’(1977). A. Funke, G. Funke, and B. Millet, Bull. SOC.Chim. Fr., 1524 (1961). 91 F. Duro, P. Condorelli, G. Scapini, and G. Pappalardo, Ann. Chim. (Rome) 60,383 (1970). 92 F. Duro, P. Condorelli, and G. Ronsisvalle, Ann. Chim. (Rome) 63,45 (1973).

84

85

Sec. VLA]

1,4- AND

DIHYDRO-1,CBENZOTHIAZINES

149

$-yz+;Ip.R - UN ' 'XC0'" CI

CI

H

(42) R,

R'

R' = Me, Et

atom at the 6-position on the benzothiazine ring provides a considerable stabilizing influence, preventing dimerization on hydrolysis of the ester.

4. Reaction with a-Halo Ketones and Derivatives a-Halo ketones, especially phenacyl bromides, react with 2-aminobenzenethiol as previously d e s ~ r i b e d , ' ~ ' ~although, . ' ~ * ~ ~as~explained ~~ in Section I, these reactions are not always straightforward." This method does, however, represent one of the simplest routes to benzothiazines. Using 2hydroxyphenacyl halides, Curtze and Thomas prepared the benzothiazine 43, which on treatment with acetic anhydride cyclized 44.95

CH, (43)

(44)

a-Halo car bony1 compounds, when used in the protected acetal form,'o~3'*94*96 give the unsubstituted parent ring 8, which cannot be isolated OEt

K. Fuji, Yakugaku Zasshi 77,347(1957)[CA 51, 12100 (1957)l. C. Santacroce,D. Sica, and R. A. Nicolaus, Gazz. Chim. ltal. 98,85(1968). 9 5 J. Curtze and K. Thomas, Liebigs Ann. Chem., 328 (1974). 96 F.Chioccara, G . Prota, and R. H. Thomson, Tetrahedron Lett., 811 (1975). 93

94

150

C. BROWN AND R. M. DAVIDSON

[Sec. V1.A

owing to its instability. While this route, employing TFA as the catalyst, does lead to the formation of 8 in solution, the product decomposed easily to a variety of products, including 2-methylbenzothiazole and the dye 45." Use of aqueous HCI leads to the trimer 21.37

(45)

A thermally stable polymer (47) based on the 1,Cbenzothiazine ring has been prepared, using a bis-a-halo ketone and the diphenyl derivative 46. This polymer has a molecular weight of between 10,000and 20,000 and is stable up to -350°C in air.97

HsmsH +QCOCH,Br

H2N

\

NHZ

COCH,Br

5. Reactions with I ,3-Diketones and P-Keto Esters When DMSO is the solvent, 1,3-diketones and /?-keto esters react with 2In*benzene or methaminothiophenol to give 4H-l,6benzothiazines (a).' anol, however, benzothiazolines such as 49 are produced according to the work of Kiprianov and P ~ r t n y a g i n a .An ~ ~ oxidative cyclization mechanism P. Bottex, B. Sillion, and G . de Gaudemaris, C. R. Hebd. Seances Acad. Sci., Ser. C 267, 71 1 (1968). S. Miyano, N. Abe, K. Sumoto, and K. Teramato, J.C.S. Perkin I , 1146 (1976). 9 9 A. I. Kiprianov and V. A. Portnyagina, Zh. Obshch. Khim. 25, 2257 (1955) [ C A 50, 9378 (1950)]. "

Sec. VLA]

1,4- AND DIHYDRO-1,CBENZOTHIAZINES

151

involving an intramolecular nucleophilic attack on an enamino ketone (50) was postulated to account for the results in DMS0.98This procedure has been used in the preparation of a series of 4H-1,4-benzothiazines 48 substituted in the aromatic ring or carrying fluorine in the side chains.'OO*'O'

R, R'

=

Me, Ph, OEt

H

6 . Reaction with Other Compounds Reactions of 2-aminobenzenethiol with a variety of other compounds provide the 1,4-benzothiazine ring system. An early report by Langlet claimed that the reaction with ethylene dibromide gave dihydro-1,4-benzothiazine (51).'02 However, more recent work by Santacroce indicates the product is 2methylbenzothiazole (52).94'However, 1,2-dichloroalkenes have been employed successfully by Kaul in the preparation of heterocyclic dye 53 having the 1,4-benzothiazin-3-one ring.35

lo'

R. R. Gupta, K. G. Ojha, G . S. Kalwania, and M. Jumar, Heterocycles 14, 1145 (1980). R. P. Soni and M. L. Jain, Tetrahedron Lett. 21, 3795 (1980).

lo*

N. A. Langlet, Bi. Suen. Vetenskaps akad. H a n d . 2211, No. 1,8 (1896) [Beilstein 27,343.

loo

152

[Sec. V1.A

C. BROWN AND R. M. DAVIDSON

aSH +fr

\

NH,

Br

\

N

O

0 (53)

Hirano et al. prepared 2,3-dihydro-3-imino-4H-1,4-benzothiazine (55), using chloroacetonitrile under acid condition^'^^ via the intermediate 54, previously assigned structure 55 by Riolo. lo4 These workers also reported the intriguing conversion of the benzothiazolium salt (56) to 4-methyl-3iminodihydro-l,4-benzothiazine(57). O 3 This reaction appears to involve

'03

Io4

H. Hirano, M. Takamatsu,K. Sugiyama, and T. Kurihara, Chem. Pharrn. Bull. 27,374(1979). C. B. Riolo, Ann. Chim. (Rome)45, 1174 (1955).

Sec. VI.A]

153

1,4- AND DIHYDRO- 1,CBENZOTHIAZINES

prior deformylation of the nitrogen, in contrast to the work previously reported by Friedrich' (see Section V1,B). 2,3-Diimino-4H-1,4-benzothiazine (58) has been prepared by Weidinger and Kranz, starting from dimethyl oxaldiimidate.

NH

I

Me

I

Me

Me

(3)

Miyano et al. observed an interesting cyclization of the vinylogous thiol ester (59), prepared from 2-aminobenzenethiol and 3-chloro-5,5dimethylcyclohex-2-enone. On heating in DMSO, 59 gave benzothiazine 60. A

I

ayJ H

lo'

0

H. Weidinger and J. Kranz, Chem. Ber. 97,1599 (1964).

T H

154

[Sec. V1.B

C. BROWN AND R. M. DAVIDSON

route involving the rearrangement of 59 to 62 via the spiro compound 61, followed by oxidative cyclization of 62, was propo~ed.’~

B. PREPARATION BY RINGEXPANSION 2-Aminobenzenethiol reacts readily with carbonyl compounds to give 1,3benzothiazoles (63).Io6 Certain derivatives of this ring system have been found to undergo ring expansion under specific conditions to give benzothiazines. The first report in the literature of this type of reaction involved the treatment of benzothiazolium salt 64 with base; the postulated mechanism12 is shown in Scheme 1.

Br- I CH,COPh

I

CH,CH,CI

I

CH,COPh

I

CH,CH,CI

I

CHO

I

CHO

SCHEME 1

On the other hand, treatment of N-(2-chloroethyl)benzothiazoliumsalt 65 with base affords the N-formyldihydro- 1,Cbenzothiazine 66 through ring

*06

R. C. Elderfield, ed., “Heterocyclic Compounds,”Vol. 5, p. 506. Wiley, New York, 1957.

Sec. VI.B]

1,4- AND

DIHYDRO-1,4-BENZOTHIAZINES

155

closure by S-alkylation."' Treatment of 3-methylbenzothiazolium with phenacyl bromide in the presence of triethylamine also results in ring expansion and formation of a 1,4-ben~othiazine."~ Chioccara et al. reported ring expansion of benzothiazoline derivatives (67), using sulfuryl chloride in anhydrous dichloromethane to give N-acetylated lP-benzothiazines (69)accompanied by small quantities of the corresponding keto sulfides (68), which could also be cyclized in the presence of acid to the benzothiazines (69).The presence of keto sulfides was ascribed to ring opening of the intermediate benzothiazinyl cations by traces of water in the "dry" dichlor~methane.'~~ In the case of 67 (R = Ph, R' = Me), two isomeric thiazines (70 and 71) in the ratio 3:l were obtained, elimination of the benzylic proton evidently being little favored over elimination of the methyl proton in

J

I

Ac

Ac

0

I

Ac

Ac

lo'

H.-J. Federsel and J. Bergman, Tetrahedron Lett. 21,2429 (1980).

lo'

J. A. Van Allen, J. D. Mee, C. A. Magguilli, and R. S. Menion, J . Heterocycl. Chem. 12, 1005

log

(1975). F. Chioccara, R. A. Nicolaus, E. Novellino, and G . Prota, Chim. Ind. (Milan) 58,546(1976).

156

C. BROWN AND R. M. DAVIDSON

[Sec. V1.B

formation of the intermediate thiazinyl cations.' l o Similar reactions in dry diethyl ether give comparable yields." 'Jl2 It was subsequently observed that when an excess of sulfuryl chloride was employed instead of 1 equivalent, the product was the dimer 2,2'-(ethane-1,2diy1idene)-bis-1,Cbenzothiazine (72), with the cyanine dye linkage."

Ac (72)

Benzothiazolines undergo ring expansion in boiling DMSO to give 4H-1,4benzothiazines (73)in low to moderate yield.' l4 Similar treatment of Nacetylated benzothiazolines results in an N -,C acyl migration to give the benzothiazoles (74), rather than N-acylbenzothiazines." It is possible to transform in low yields benzothiazolines to 2,3-dihydro-4H- 1,4-benzothiazin3-ones, using chloroacetyl chloride.'

'

-

QJ-BHd"

Q\ J~m)"CoR

I

COR (74)

Prota et al. and a group in Japan independently reported ring expansion reactions of benzothiazoline S-oxides, which are mechanistically similar to the F. Chioccara, G. Prota, R. A. Nicolaus, and E. Novellino, Synthesis, 876 (1977). F. De Simone, A. Dini, E. Ramundo, and G. La Bella, Rend. Accad. Sci. Fis. Mat., Naples 44, 387 (1977) [ C A 90,54891 (1979)l. 11* F. De Sirnone, A. Dini, R.A. Nicolaus, E. Ramundo, M. Di Rosa, and P. Persico, Farmaco, Ed. Sci. 35,333 (1980) [ C A 93, 132429 (198O)l. ' I 3 F. Chioccara, V. Manciacapra, E. Novellino, and G. Prota, J.C.S. Chem. Cornmun.,863 (1977). 114 G. Liso, G. Trapani, A. Latrofa, and P. Marchini, J . Heterocycl. Chem. 18,279 (1981). 'I5 G. Liso, G. Trapani, A. Reho, and A. Latrofa, Tetrahedron Lett. 1641 (1981). M. Hori, T. Kataoska, M. Shimizu, and Y . Irnai, Heterocycles 9, 1413 (1978). 110

Sec. VI.B]

1,4- AND DIHYDRO-l,4BENZOTHIAZINES

157

'

sulfuryl chloride reactions described above. 7-' 2o These Italian workers reported fair yields of N-acetyl-4H-l,4-benzothiazines(69) from the Nacetylbenzothiazolines 67 on treatment with 3-chloroperbenzoic acid in chloroform.l17 The reaction appears to work equally well for either the cis or trans isomers of the initially formed sulfoxides but, apart from one case, does not appear to offer any significant advantage over the sulfuryl chloride procedure. Hori et al. reported the ring expansion of 3-acetylbenzothiazoline 1-oxide (75)in refluxing acetic anhydride' 8-'20 to give 4-acetylbenzothiazines (76)via a sulfenic anhydride intermediate; this reaction is nonstereospecific, supporting the proposed nonconcerted mechanism.

'

0

?H

Ac

Ac

,

(75)

OAc I

AC

Ac

The reaction is unusual in that sulfoxides processing an a-hydrogen atom normally undergo a Pummerer reaction under these conditions to form the acetoxy sulfide. The reaction can be compared with the Morin rearrangement of penicillin sulfoxide to cephalosporins.' 2 1 Ring expansion of benzothiazoles (77) with dimethylacetylenedicarboxylate (DMAD) in aqueous methanol requires water as an essential agent to F. Chioccara, L. Oliva, G. Prota, and E. Novellino, Synthesis, 744 (1978). M. Hori, T. Kataoka, H. Shimizu, and Y. Imai, Chem. Pharm. Bull. 27, 1982 (1979). L 1 9M. Hori, T. Kataoka, H. Shimizu, Y. Imai, and N. Ueda, Fukusokan Kagaku Toronkai Koen Yoshishu, 1 2 4 61 (1979) [ C A 93,71673 (1980)l. lZo M. Hori, T. Kataoka, H. Shimizu, and N. Ueda, Tetrahedron Lett. 22, 1701 (1981). Iz1 P. G. Sammes, Chem. Rev. 76, 113 (1976). 'I'

IL8

158

[Sec. V1.B

C. BROWN AND R. M. DAVIDSON

trap the benzothiazolium zwitterion intermediate 78 in contrast to the routes already described, which rely on anhydrous conditions.' 2 2

(77)

(78)

\

- poH X

%H

Me0,C

COzMe

Preparation by ring expansion can be contrasted with that of ring contraction recently reported, whereby 1,6-benzothiazocine derivatives (79) undergo ring contraction in the presence of lead tetraacetate to give the 2 H 1,Cbenzothiazine derivatives 80 and 81. The proposed mechanism for the reaction involves a transannular sulfur migration. The structure of 81 was confirmed by X-ray crystallography.' 2 3

A. McKillop, T. S. B. Sayer, and G . C. A. Bellinger, J . Org. Chem. 41, 1328 (1976). J. B. Press, N. H. Eudy, F. M. Lovell, and N. A. Perkinson, Tetrahedron Lett. 21,1705 (1980).

Sec. VI.C]

1,4- AND DIHYDRO- 1,4-BENZOTHIAZINES

159

c. PREPARATION FROM 2-NITROBENZENETHIOLS Syntheses of the heterocycle from 2-nitrobenzenethiol involving reductive cyclization methods have been employed by a number of research groups.

1. Reaction with Unsaturated Carbon-Carbon Bonds 2-Nitrobenzenethiol will add across the double bond of maleic anhydridelZ4; the adduct can then be cyclized in the presence of zinc and acid (82). Similar studies acetic acid to give 1,4-benzothiazin-3-one-2-acetic with citraconic acid and the acid anhydride, where the thiol added predominantly to the position /3 to the methyl in contrast to an earlier report,125gave the citraconic anhydride and acid adducts. When treated with zinc and acetic acid, the adducts formed diastereoisomers (83a and 83b) of 1,4-benzothiazin3-onepropanoic acid.

H

2.

Reaction with a-Halo Acids and Esters

As early as 1897, Friedlander treated 2-nitrobenzenethiol with chloroacetic acid to obtain the thioacetic acid adduct, which then was cyclized with zinc in acetic acid to dihydro-l,4-benzothiazin-3-0ne.~~~ A similar synthesis by J. Bouroais, C. R. Hebd. Seances Acad. Sci. Ser. C 262,1701 (1966). F. B. Zienty, B. D. Vineyard, and A. A. Schleppnik, J . Org. Chem. 27,3140(1962). H. Friedlander and C. Chwala, Monatsh. Chem. 28,271 (1897).

160

[Sec. V1.C

C. BROWN AND R. M. DAVIDSON

Claasz generated the mercaptan in situ from the disulfide. CIaasz also treated a-bromo esters with the thiol and subjected the adducts to reductive cyclization, which produced the benz~thiazinones.'~~ A different reduction was employed by Coutts et al. on 842sodium nitrophenylthio) esters to give hydroxamic acid derivatives (a), borohydride with palladium-charcoal being used to effect the cyclization.' 28

OH

OH

(W

(85)

Angelini described the preparation of dihydro- 1,Cbenzothiazine and related compounds from analogous esters by a two-stage reduction using tin and HCl or lithium aluminum h ~ d r i d e . 'It~ is ~ interesting to compare the reaction of 2-nitrophenol with similar reagents to produce benzooxazine derivatives. 2-Nitrophenol reacts with a-bromoethyl acetate, and the adduct is cyclized with zinc and ammonium chloride to the hydroxamic derivative 85.I3OThe adduct with phenacyl chloride has been similarly cyclized under a variety of

3 . Reaction with Halides 4H-1,4-Benzothiazine 1,l-dioxide (87) has been prepared by the action of ally1 bromide on the sulfinic acid 86, followed by ozonolysis and catalytic hydrogenation.20

M. Claasz, Chem. Ber. 45, 2424 (1912). R. T. Coutts, H. W. Peel, and E. M. Smith, Can. J . Chem. 43,3221 (1965). C. Angelini and G .Grandolini, Ann. Chim. (Rome) 46,235 (1956). E. Honkanen and A. Virtanen, Acta Chem. Scand. 14, 1214 (1960). 1 3 1 P. Battistoni, P. Bruni, and G . Fava, Synthesis, 220 (1979). 13' P. Battistoni, P. Bruni, and G . Fava, Tetrahedron 35, 1771 (1979).

Sec. VI.D]

1,4-AND DIHYDRO-l,4BENZOTHIAZINES

161

Fusco reported to have prepared 3,4-dihydro-1,4-benzothiazine by treating 2-nitrobenzenethiol with /?-chloroethanol and cyclizing the intermediate with tin and hydrochloric Later work, however, showed the product to be 2(2-aminophenyIthio)ethan01.8~-~~*~~

4. Other Reactions with the SH Group In addition to the 2-amino and 2-nitro derivatives, various other substituted benzenethiols have been used as precursors for the benzothia(88) has been prepared zine system. 6,7-Dimethoxy-1,4-benzothiazin-3-one 1 . CICHzCOzH

Me0

3. Sn/HCI

H

from 3,4-dimethoxyben~enethioI.'~~ 2-Chlorobenzenesulfinic acid, a-bromoacetone, and ammonia give 3-methyl-4H- 1,4-benzothiazine 1,l-dioxide (89). 34

'

D.

PREPARATION FROM 2-NITROBENZENESULFENYL CHLORIDES

All of the synthetic routes reviewed so far have primarily involved the use of sulfur as a nucleophile. Sulfur can also act as an electrophile in the formation of precursors of the benzothiazine ring system. Reaction of sulfenyl chloride with ketones gives /?-keto sulfides. The acetophenone adduct 90 has been cyclized with stannous chloride and hydrogen chloride in acetic acid to give 3phenyl-6-chloro-2H-l,4-benzothiazine (91).' 35 133

K. J. Baldick and F. Lions, J . Proc. R. SOC.N.S.W! 71, 112 (1938)[ C A 32,34006(1938)J

134

G.Pagani and S. Maiorana, Chim. Id.(Milan) 53,468 (1971). T.Zinke and J. Baeumer, Justus Liebigs Ann. Chem. 416,86(1918).

13'

162

C. BROWN AND R. M. DAVIDSON

[Sec. V1.D

Dihydro-1,4-benzothiazineshave been prepared in good yield by catalytic reduction of fi-keto sulfides at elevated temperatures and pressures using a variety of catalyst^.'^ Coutts et al. unsuccessfully attempted to prepare benzothiazines by reductive cyclization of 8-keto sulfides with sodium borohydride or palladium-charcoal. They isolated only the 8-(2-nitrophenylthio) alcohol^,^ in contrast to the successful synthesis of the desired ring by the same reduction of fi-(2-nitrophenylthio) esters.128A wide range of 8-keto sulfides has been successfully reduced to dihydro- 1,Cbenzothiazines, using tin and hydrochloric acid, in either glacial acetic acid or ether solution.*’ The sulfide 92, prepared by treatment of N-methyl-3-methylindole with 2nitrobenzenesulfenyl chloride, was converted to the rearranged benzothiazine 93 by treatment with triethyl phosphite under nitr~gen.’~’

Me

1,3-Diketones are also readily sulfenylated in the 2-position by benzenesulfenyl halides, and Shvedov et al. have reported the reductive cyclization of products such as 94 with zinc in acetic acid to benzothiazines

R. T. Coutts, S. J. Matthias, and H. W. Peel, Can. J . Chem. 48,2448 (1970). A. H. Jackson, D. N. Johnston, and P. V. R. Shannon, J.S.C. Chem. Commun., 911 (1975).

Sec. VI.E]

1,4-AND DIHYDRO-l,4-BENZOTHIAZINES

163

95.13' However, attempts to reduce the analogous product from 2,4together with 2pentanedione gave 3-methyl-3,4-dihydro-1,4-ben~othiazine~' methylbenzothiazole. The latter had previously been reported to be the product of this reduction, using stannous chloride.'

E. PREPARATION FROM DISULFIDES, CYSTEINE DERIVATIVES, AND

OTHERREAGENTS

It has been found possible to construct the 1,Cbenzothiazine ring by direct interaction of bis-(2-aminobenzene) disulfide (96) with carbonyl comp o u n d ~ . ' The ~ ~ reaction ~ ' ~ ~ is most efficient when conducted under a nitrogen atmosphere with a 1:l ratio of reactants; otherwise, the principle products are benzothiazoles. While reduction of the benzothiazine 97 with sodium borohydride gives a stable dihydro derivative, the unsaturated benzothiazines themselves were prone to autoxidation, giving rise to benzothiazoles and benzothiazine sulfoxides.14'

The postulated mechanism for the formation of the 1,4-benzothiazine ring involves the formation of the imine 98, followed by cleavage of the disulfide bond (see Section VI,A,5). This reaction is general for keto compounds, P-keto esters,142and acetylenic ketones and esters'43; the heterocycle is produced in yields of 70430%. V. I. Shvedov, L. B. Altukhova, V. M. Lyubchanskaya, and A. N. Grinev, Khim. Geterosikl. Soedin., 1509 (1972)[CA 78,43395(1973)J V. Carelli, P. Marchini, F. Micheletti-Moracci, and G. Liso, Tetrahedron Lett., 3421 (1969). I4O V. Carelli, P. Marchini, M. Caroellini, F. Micheletti-Moracci, G. Liso, and M. G. Lucarelli, Tetrahedron Lett., 4619 (1969). V. Carelli, F.Micheletti-Moracci, F. Liberatore, M. Cardellini, M. G. Lucarelli, P. Marchini, G. Liso, and A. Reho, In?. J . Sulf: Chem. 8,267(1973). 142 P. Marchini, G. Trapani, G. Liso, and V. Berardi, Phosphorus and Sulphur 3,309(1977). G. Liso, G.Trapani, V. Bernardi, and P. Marchini, J . Heterocycl. Chem. 17,377(1980). 138

164

C. BROWN AND R. M. DAVIDSON

[Sec. V1.E

aNHz D:7J;ozR Y2R

S

I

Q J H 2

+Ill CO2R I

\

H

+

The involvement of cysteine in the biosynthesis of phaeomelanins and trichochromes, natural pigments in mammals, has prompted work on the reaction of cysteine with a variety of reagents to produce the 1,4-benzothiazine ring system.

Sec. VI.F]

1,4- AND

165

DIHYDRO-1,CBENZOTHIAZINES

Cysteine ethyl ester (99) reacts with p-benz~quinone~l to give a dimeric product (100) and not the quinonoid structured product (101) as reported by Kuhn and Hammer.’44 The reaction of “epoxydon” (102) with cysteine hydrochloride has been found to give a 1,4-benzothiazine derivative (103).145 OH

The formation of the 1,4-benzothiazin-3-one (104) has been observed in the course of sequential analysis of proteins, using 2-methyl-N-benzenesulfonylN’-bromoacetylquinone diimide.’46 The protein chain is cleaved at the cysteine amino acid unit, with cysteine forming a benzothiazinone with the diimide reagent. NS0,Ph

I +

-

H PhSO2N)/J~~ Me

0 H

NCOCH,Br (104)

F. OTHERROUTES

’

Various other routes have been reported to give the 1,Cbenzothiazine ring, some of which are summarized below. Synthesis of the 1,Cbenzothiazine 1,ldioxides (105) from benzaldimine and methylene sulfone ylide has been reported.14’ R. Kuhn and I. Hammer, Chem. Ber. 84,91 (1951). K. Nabeta, A. Ichihara, R. Sakai, and S. Sakumara, Agric. Biol. Chem. 36, 2261 (1972). 146 T. J. Holmes and R. G. Lawton, J . Am. Chem. Soc. 99,1984 (1977). 14’ M. Rai, S. Kumar, K. Krishan, and A. Singh, Chem. Ind. (London),26 (1979).

144

14’

166

C. BROWN AND R. M. DAVIDSON

[Sec. V1.F

(105)

An attempt to prepare triorganoantimony compounds containing tridentate ligands failed as a result of their spontaneous decomposition to ( 106).148 triorganostibenes R,Sb and 2-acetyl-3-methyl-4H-1,4-benzothiazine

H

The formation of thiazine was explained in terms of the previously observed instability of triorganoantimony dimercaptides, which spontaneously decompose with the formation of R,Sb and RSSR.149s's0 Secondary amine derivatives containing sulfur have been cyclized to give 1,4-benzothiazine rings. Cyclization under base conditions have been studied by Knyazev et a/., using l-(/?-N-aminoethyIthio)-2,4,6-trinitrobenzene (107). On cyclization, this produced 6,8- (108) and/or 5,7-dinitro-4-methyl-2,3dihydro-1,4-benzothiazine(109), the ratio of isomers produced depending on the base and solvent used to effect cyclization."' The secondary amides 110 can also be cyclized to give the 1,4-benzothiazine ring. Heating at 180-200°C produced 1,4-benzothiazin-3-one, which on treatment with lithium aluminum hydride gave dihydr0-1,4-benzothiazine.'~~ '41

F. Di Bianca, E. Rivarola, A. L. Spek, H. A. Meinema, and J. G . Noltes, J. Organomer. Chem. 63,293 (1973).

Y. Matsumara, M. Shindo, and R. Okawara, Inorg. NucL Chem. Lett. 3,219 (1967). H. Schmidbaur and K. Mitschke, Chem. Ber. 104,1824(1971). ''I V. N. Knyazev, V. N. Drozd, and V. M. Minov, Tetrahedron Lett., 4825 (1976). ''* R. N. Prasad and K. Tietje, Can. .I. Chem. 44, 1247 (1966). 149

SeC.

VII.A]

1,4- AND

DIHYDRO-1,4-BENZOTHIAZlNES

R

=

167

Me. Ph

CHzR

I

H (110)

R

=

H, Me, Ph; X

= CI, Br

As outlined in Section 11, the reaction between benzoquinones, or their phenolic precursors, and 2-aminoethanethiols leads to a variety of benzothiazines, depending on reaction ~ o n d i t i o n s . ~ l - ~ ~

VII. Reactions of 1,4Benzothiazines The 1,Cbenzothiazines do not have a particularly well studied chemistry; with certain exceptions (see below), most efforts have been expended on their preparation. However, some reactions have received some attention, and these are summarized in this section.

A. N-ALKYLATION AND N-ACYLATION N-Alkylation of the 4H-1,Cbenzothiazine 95 has been r e ~ 0 r t e d . l ~ ~ Kiprianov et al. described the quaternary salts of some 2H-1,4-benzothiazines which are less conveniently prepared by direct N-alkylation than by synthesis

168

C. BROWN AND R. M. DAVIDSON

[Sec. VI1.A

from the appropriate N-substituted 2-aminobenzenethiols and a-halo

ketone^.^^*'^^ Dihydro-1,4-benzothiazines are generally more reactive, and direct Nalkylation has been reported, but this reaction is not always straightforward.2' Funke et al. could not alkylate 2-phenyldihydro-1,4-benzothiazinewith wchloramines, even under forcing condition^.'^ However, later work showed that this reaction was possible in toluene solution,57and other workers have also reported direct alky1ati0ns.l~~ The 1,4-benzothiazin-3-ones are, however, more easily alkylated, and reduction of the N-alkyl derivatives of these compounds, usually with lithium aluminum hydride, affords the correspond"These products can also ing N-alkyldihydro-1,4-benzothiazines.sz*56~70~go*' be prepared in one step from the corresponding 1,4-benzothiazines, e.g., 111 -+ 112, presumably via intermediate dihydro-1,4-benzothiazines,by sodium borohydride in the presence of a carboxylic acid. Boron derivatives, such as Na[(RCOO),BH] and Na[(RCOO)4B] are suggested as the species responsible for N-C bond f ~ r m a t i o n . " ~

Et

N-Acylation of dihydro- 1,4-benzothiazines is, however, a smooth process, and most of the usual reagents and reaction conditions have been successfully " Reduction of the acyl derivatives with lithium aluminum hydride affords the corresponding N-alkyl corn pound^.^^^' 5 2 Hirano' observed that when attempting to prepare the acetyl derivatives of 2,3-dihydro-3-imino-4H-1,4-benzothiazine (55) with acetic anhydride, the product obtained was bis-[ 1,4]-benzothiazino [3,2-b; 2'3'-el pyridine (113). A similar reaction' O3 with 4-methyl-34minodihydro- 1,Cbenzothiazine (114) produced 6,7,9,16-tetramethy1-8,15-diazophenothiazino [8,7-h]-phenothiazine (115).

A. 1. Kiprianov and Z. N. Pazenko, Zh. Ohshch. Khim. 21, 156 (1951)[CA 45,7574(195l)l. J. Piechaczeck and H. Bojarska-Dahlig, Acra Pol. Pharm. 24,244(1967)[ C A 69,19098(1968)l. (1968)l. P. Marchini, G.Liso, and A. Reho, J . Org. Chem. 40,3453 (1976). H. Hirano, K.Sugiyama, S. Nagata, and T. Kurihara, Chem. Pharm. Bull. 27,2488(1979).

IJ3

SeC. VII.B]

1,4- AND DIHYDRO-1,4-BENZOTHIAZl”S

I

169

I Ac

Ac

/N

I Me

Me

Me

(115)

(114)

N-Acyl-2,3-dihydro-1,4-benzothiazinesand the related phenothiazines react with both organolithium and organomagnesium reagents to give the 8dicarbonyl derivative 116, indicating that the N-acyl derivatives may have a role to play as useful acylating agents.’ 5 7 Mechanistic studies have provided novel explanations for this behavior and that of the related 1-oxides and 1,ldioxides (117).15*

COCH,COMe

(116)

COMe (117)

X = SO, SO,

B. ELECTROPHILIC SUBSTITUTION There have been relatively few reports of electrophilic substitution reactions with this system. One example is the reaction of the indolobenzothiazine 118

”’F. Ciminale, L. DiNunno, and S.Florio, Tetrahedron Lett., 3001 (1980). ”*

S. Florida, J. L. Leng, and C. J. M. Stirling, J . Heterocycl. Chem. 18,857 (1981).

170

C. BROWN AND R. M. DAVIDSON

[Sec. VI1.B

with oxygen to give the spirooxindole 119. This may proceed via the electrophilic attack of oxygen on the activated 2-position of 118 to give the hydroperoxide 120 and hence 119 via the hydroxy species 12LL3' The analogous autoxidation reaction of simpler benzothiazines to give 2-acylbenzothiazolines has been shown to be a radical chain proce~s.'~'

Me (120) X = O H (121) X = H

4H- 1,CBenzothiazine 1,l -dioxide undergoes a variety of electrophilic substitutions, including nitration, bromination, Vilsmeier formylation, and the Mannich reaction. All substitutions occur at the 2-position, and an analogy with indole was drawn by the authors.20 3,4,-Dihydro-2H-1,4-benzothiazin-3-oneand N-alkyl derivatives have been chlorinated, also in the 2-position, with sulfuryl chloride in dichloromethane.lS9Reaction of the first-mentioned of these with Vilsmeier reagent yields the chlorinated product 122,l6' which hydrolyzes to give a variety of benzothiazine products, depending on the reaction conditions.161 2-Alkylidene derivatives 123 have been prepared by condensation of benzothiazin-3-ones with aldehydess2 and by reductive cyclization of the Quaternary salts of benzothiazines also condense readily nitro acids 124.162

J. W. Worley, K. W. Ratts, and K. L. Cammack,J. Org. Chem. 40, 1731 (1975). M. R. Chandramohan, M. S . Sardessai, S . R. Shah, and S. Seshadri, Indian J . Chem. 7 , 1008 ( 1969). S. R. Shah and S. Seshadri, Indian J . Chem. 10,820 (1972). V. Baliah and T. Rangarajan, J . Chem. SOC.,4703 (1960).

SeC. vII.c]

171

1,4-AND DIHYDRO-1,4-BENZOTHIAZINES

with p-dimethylaminobenzaldehyde to give intensely colored styryl products such as lZ.163

Me

Me

C. NUCLEOPHILIC SUBSTITUTION Nucleophilic attack on the 2-chlorine of 126 by triethyl phosphite accounts for the formation of the phosphonates 127, which are useful in the synthesis of 2-alkylidene derivatives analogous to 123 via the Wadsworth-Emmons reaction.'''

I

I

R

R

(1%)

(127)

The Vilsmeier product 122 also undergoes nucleophilic displacement of the 3-chlorine when treated with amines in acetic acid containing pyridine. The ultimate product is the aldehyde 128 via the pyridinium salt 129.164

-'

usIcHo

(13)

N H

NHAr

(128)

Nucleophilic substitution of hydrogen by chlorine in the 7-position occurs when the N-hydroxy derivative 130 is treated with hydrochloric acid, 164

A. I. Kiprianov and Z. N. Pazenko, Zh. Obshch. Khim. 21,170 (1951)[ C A 45,7576 (1951)l. S. R. Shah and S. Seshadri,Indian J . Chem. 10,977(1972).

172

C. BROWN AND R. M. DAVIDSON

[Sec. VI1.D

probably via 131, to give the product 132 as shown be10w.I~~ When the 7position is blocked, as in 133, the reaction does not occur.166

(130) R = H

(133) R = Me

6-Amino-2,3-dihydro-1,4-benzothiazin-3-one(134) is a useful source of a wide variety of 6-substituted derivatives via diazotization. The amino group has been replaced by halogens and pseudohalogens, by NO, and by NO,, as well as by HgCI, H,As03, and H2SbOJ.61

D. REARRANGEMENT REACTIONS Benzothiazines have been reported to undergo a number of rearrangement reactions, one of the most commonly encountered involving ring contraction. Thus among the products of autoxidation of 1,4-benzothiazines are benzothiazoline derivative^.'^^^'^'^^^^ For example, the benzothiazine 135 on treatment with oxygen in acidified cyclohexane gave the acyl derivative 136.

16'

16'

R. T. Coutts and N. J. Pound, Can. J . Chem. 48, 1859 (1970). R. T. Coutts, S. J. Matthias, E. Mah, and N. J. Pound, Can. J . Chem. 48,3727 (1970). G. Liso, P. Marchini, A. Reho, and F. Micheletti-Moracci, Phosphorus and Sulphur 2, 117 (1976).

SeC.

VII.D]

1,4- AND DIHYDRO-1,4-BENZOTHIAZl"S

173

The intermediacy of hemithioketals was indicated by the isolation of the analogous species 137, which could be converted to the thiazoline 138.

As might be anticipated, derivatives fully substituted at the 2-position are not prone to such autooxidation, even when the 3-substituent has a 8hydrogen, as in 139, thus supporting the contention that a radical mechanism via a species such as 140 0 ~ e r a t e s . l ~ ~ Ring contraction has also been observed in hydrogenation reactions of benzothiazines. Catalytic hydrogenation of 3-phenyl-2H-l,4-benzothiazine (141) gave 2-methyl-2-phenylbenzothiazoline(142), and not the dihydro-1,C benzothiazine as might have been expected.14

(141)

(142)

A thiophenol intermediate is assumed to participate in the formation of the benzothiazole ring, this being consistent with the mechanism postulated for hydrogenolytic thiazine-thiazole rearrangement.I6' Benzothiazines (143) prepared from 8-keto esters and disulfide will react further under acid-catalyzed, thermal conditions to give an isomeric product (144) derived via a [1,3]-sulfur shift.14*

16*

D. Sica, C. Santacroce, and R.A. Nicolaus, Gazz. Chim. ltal. 98,488 (1968).

174

C. BROWN AND R. M. DAVIDSON

[Sec. VI1.D

(144)

The last reaction can be compared with the Grignard reagent-induced conversion of the 1,4-benzothiazin-3-one 145 to the dihydro- 1,4benzothiazine 146. The a,S-unsaturated ketone 147 was postulated as an intermediate to account for this rearrangement.'*

(145)

(147)

(146)

Coutts and Pound observed the isomerization of 148 to 149 with glacial acetic acid, presumably by the route i n d i ~ a t e d . ' ~ ~

(148)

( 149)

Configurational isomerism in 2-methylene derivatives can be induced photochemically as demonstrated by the conversion of Z isomer 150 to its E isomer 151. The E isomer undergoes a facile thermal dimerization to form the cyclobutane derivative 152.80-170 R. T. Coutts and N. J. Pound, J. Chem. Soc. C, 2696 (1971). Y. Maki and M. Sako, Chem. Pharm. Bull. 24,2250 (1976).

SeC.

VII.E]

175

1.4- AND DIHYDRO-l,4BENZOTHIAZINES

Nn

Me

I

C0,Me

alezMe Me0,C

asyH ‘ N

O

I

&

a\ :$02Me

\

I

I

Me

Me

E.

Me

OXIDATIVE COUPLING OF 1,4-BENZOTHIAZINES

Difficulties are often encountered in the preparation of even quite simple l,Cbenzothiazines, and it is now clear that these can often be explained in terms of readily occurring oxidative coupling reactions of the ring. Indeed, many early methods for the synthesis of 1,6benzothiazines do, in fact, yield the dimers.” Dehydrodimers are important as the basis of the naturally occurring pigments, the trichochromes discussed in Section 11. Such dimers were first reported by Fujii, who, on attempting the preparation of the picrate from 3-phenyl-ZH-l,Cbenzothiazine,isolated a dimeric species which he formulated as 153 (X = H, Ar = Ph) with unspecified stereochemistry. He also reported the 6-chloro analogue 153 (X = C1, Ar = Ph), which formed spontaneously from the monomeric t h i a ~ i n e . ~ ~

(153)

(154)

Some time later, Bottex et al., observed a similar phenomenon: the dimer 153 (X = H, Ar = Ph) formed readily from solutions of the monomer in ethanol, pyridine, or ether in the presence of air, or from heating in benzene with diethyl azodicarboxylate. Ether solutions protected from air did not yield the dimer. On the basis of limited NMR evidence, these authors formulated

176

C. BROWN AND R. M. DAVIDSON

[Sec. VI1.E

their dimer as 154.13Wilhelm and Schmidt also obtained this dimer, which they f ~ r m u l a t e d ’as~ the symmetrical structure 153,subsequently confirmed by NMR and X-ray studies.jg These studies also indicated the meso stereochemistry for 153 (X = H, Ar = 4-BrC,H4). With the exception of Bottex et al., all workers assign the 2H-l,4-benzothiazine structure to both monomeric and dimeric products. However, Duro et al. have shown that the 4H-1,Cbenzothiazine 155 also forms a 2H dimer (lS6).92

(155)

(156)

With more powerful oxidizing agents, such as chloranil, benzothiazines can (157and be converted to the dehydro dimers A2*2’-bis-(2H-1,4-benzothiazines) 158). These isomeric species interconvert readily even at ambient tempera t u r e ~The . ~ ~structures were confirmed by X-ray analysis, and the cis isomer is shown to predominate at room temperature.

(157) R = Ar (159) R = H

(158) R = Ar (160) R = H

Subsequently, it was discovered that even exposure to air was sufficient to convert the parent compound, 2H-1,4-benzothiazine 8,to the trans dimer 159, a yellow-orange solid. Solutions of this isomer are photochromic, 159 interconverting readily with the cis isomer 160 on exposure to sunlight.36Such photochromism had already been observed with related natural pigments system.’ ” based on the A2*2’-bi-(2H-1,4-benzothiazine)

‘’I

P. Boldt and E. Hermstedt, 2.Naturjiorsch. Anorg. Chem., Org. Chem.,Biochem., Biophys., Biol. 22B,718 ( 1967).

ADVANCES IN HETEROCYCLIC CHEMISTRY. VOL . 38

The Chemistry of Hydantoins C. AVENDA30 L6PEZ AND G . GONZALEZ TRIG0 Departamento de Quimica Organica y Farmacbutica. Facultad de Farmacia. Universidad Complutense. Madrid. Spain

I . Introduction . . . . . . . . . . . . . . . . . . . . . . I1 . Methods of Synthesis . . . . . . . . . . . . . . . . . . . A . Introduction . . . . . . . . . . . . . . . . . . . . . B. Amino Acids or Related Compounds and Cyanate or Thiocyanate Salts: The Read Synthesis . . . . . . . . . . . . . . . . . . . C. Amino Acids and Alkyl or Aryl Isocyanates and lsothiocyanates . . . D . Amino Acids and Ureas . . . . . . . . . . . . . . . . . E. a-Dicarbonyl Compounds and Urea Derivatives . . . . . . . . . F. Bucherer-Bergs Synthesis from Carbonyl Compounds . . . . . . . Stereochemistry of the Bucherer-Bergs and Read Reactions . . . . . G . Conversion of Other Heterocyclic Compounds to Hydantoins . . . . 1. Pyrimidine Rearrangement Ring Contraction . . . . . . . . . 2. From Other Heterocyclic Compounds . . . . . . . . . . . H . Cycloaddition Reactions with Heterocumulenes . . . . . . . . . 1. Reaction with 3-Dimethylamino-2H-azirines. . . . . . . . . 2. Reaction with Nucleophilic Carbenoids or Ylides . . . . . . . 3. Reaction with 1-Oxa-4-aza- and 1,4Diazabutadienes . . . . . . 4. Reaction with Phenylacetylene . . . . . . . . . . . . . . I . Miscellaneous Methods Starting from Amino Acid Derivatives or Related Substrates . . . . . . . . . . . . . . J . Other Methods . . . . . . . . . . . . . . . . . . . . 1. Condensation of Imines with Isonitriles and Thiocyanic Acid . . . 2. Reaction of N-Cyanoamines with 1-tert-Butyl-3,3-diphenylaziridinone K . Mutual Transformations between Hydantoins and Thiohydantoins . . 111. Physicochemical Studies on Hydantoins . . . . . . . . . . . . . A . Ionization . . . . . . . . . . . . . . . . . . . . . . B. Ultraviolet Spectroscopy . . . . . . . . . . . . . . . . . C. Mass Spectrometry . . . . . . . . . . . . . . . . . . . D. Infrared Spectroscopy . . . . . . . . . . . . . . . . . . E. Nuclear Magnetic Resonance Spectroscopy . . . . . . . . . . F. Crystal Structure Determinations . . . . . . . . . . . . . . G . Quantum Mechanical Calculations . . . . . . . . . . . . . IV. Reactivity of Hydantoins and Their Derivatives . . . . . . . . . . A . Electrophilic Substitution . . . . . . . . . . . . . . . . . 1. Protonation . . . . . . . . . . . . . . . . . . . . 2. Reactions with Lewis Acids . . . . . . . . . . . . . . . 3. N-Alkylation . . . . . . . . . . . . . . . . . . . . 177

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Copyright 0 1985 by Academic Press Inc. All rights of reproduction in any form reserved. ISBN 0-12-020638-2

178

[Sec. 1I.B

c . AVENDAROL ~ P E ZAND G . GONZALEZ TRIGO 4. N-Acylation . . . . . . . . . . . . . . 5. Halogenation . . . . . . . . . . . . . . 6. Hydantoins as Heterocyclic Compounds Containing

Active Methylene Groups. . . B. Reactions with Nucleophiles. . . 1. Hydrolysis . . . . . . . . 2. Ammonolysis . . . . . . . C. Reactions with Reducing Agents . D. Other Significant Reactions . . . V. Uses and Applications . . . . . . A. Hydantoins as Medicinal Products B. Other Uses. . . . . . . . .

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,217

. 219 .219 ,221 . 222 . 224 . 224 . 224 . 227

I. Introduction Reviews of the chemistry of hydantoins (2,44midazolidinediones)appeared in 1950’ and in 1957’; the latest in 19663 deals only with thiohydantoins. Ware’s 1950 review’ is particularly exhaustive.

11. Methods of Synthesis

A. INTRODUCTION Mechanistic and preparative aspects of the formation of the hydantoin ring show considerable development since Ware’s review. Some synthetic routes previously reviewed continue to be of prime importance, especially the Bucherer-Bergs m e t h ~ d . ~

B. AMINOACIDSOR RELATED COMPOUNDS AND CYANATE OR THIOCYANATE SALTS:THEREADSYNTHESIS A large number of hydantoins and 2-thiohydantoins wtih substituents in the C-5 position as well as a limited number of N-1 substituted examples have been prepared by this route. The ring closure of the hydantoic acid intermediates (1) to hydantoins (2) is reversible, the forward reaction being

’ E. Ware, Chem. Reu. 46,403 (1950). E. S. Schipper and A. R. Day, in “Heterocyclic Compounds” (R. C. Elderfield, ed.), Vol. 5, p. 254. Wiley. New York, 1957. J. T. Edward, Chem. Org. Sulfur Comp. 2,287 (1966). H. T. Bucherer and W. Steiner, J . Prakt. Chem. 140,291 (1934); H. T. Bucherer and V. A. Lieb, ibid. 141,.5(1934).

Sec. II.B]

179

HYDANTOINS

favored by acid medium and the reverse by alkali.' Several kinetic studies have also been reported.'-' /

CO,H

R-CH

\

+KCNX NH,

H+

\KX

R-CH/CO,H - R \ NHCXNH,

H

(1)

(2)

A number of reagents convert an optically pure 2-phenylhydantoic acid to an optically active 5-phenylhydantoin. Trifluoroacetic anhydride and dilute hydrochloric acid are the reagents of choice. The temperature dependence of the kinetics of racemization of 5-phenylhydantoin in dilute hydrochloric acid supports the conclusion that the resultant products are nearly, if not entirely, optically uniform.' In a modification of the Read reaction, instead of the free amino acids, their esters or amides, and especially their nitriles, are This procedure has also been termed the Strecker method on the basis of the synthesis of the starting amino nitriles. Practically quantitative yields of 5-monsubstituted 2-thiohydantoins (7) are reported when ammonium thiocyanate is used instead of potassium thiocyanate in acetic anhydride. The amino acid is first acetylated to give 3 which is then successively converted to the mixed anhydride 4, the acyl isothiocyanate 5, and finally the 1-acetyl-2-thiohydantoin6. The acetyl group may be

\

C0,H

/ NHCOR' R-CH -C=S /L. 'CO-N

\

COOCOCH,

-

\ r s

R I COR'

H

' V. Stella aand T. Higuchi, J . Org. Chem. 38, 1527 (1973). I. B. Blagoeva, I. G. Pojarlieff, and V. S. Dimitrov, J.C.S. Perkin II,887(1978). ' F. Giiler and R. B. Moodie, J.C.S. Perkin 11, 1752 (1980).

* K. H. Dudley and D. L. Bries, J . Heterocycl. Chem. 10(2), 173 (1973).

'W. T. Read, J . Am. Chem. SOC.44,1766 (1922).

+ R'C0,H

180

C. AVENDAfiO L6PEZ AND G. GONZALEZ TRIG0

[SeC. 1I.c

removed by very mild acid or alkaline hydr~lysis.~ This reaction sequence has been applied by Schlack and Kumpf l o to remove the C-terminal amino acid of a p~lypeptide.~.'

'

C. AMINOACIDSAND ALKYLOR ARYL ISOCYANATES AND ISOTHIOCYANATES N3-Substituted hydantoins and 2-thiohydantoins (9)are prepared by acidcatalyzed cyclization of the substituted ureido or thioureido acids (8)obtained from a reaction of a-amino acids with alkyl or aryl isocyanates and isothiocyanates.'v3*12 This method has been applied to prepare 2-selenohydantoin~,'~and also in the stereospecific synthesis of (S)-( +)-1,s cyclotrimethylene-3-phenyl-2-thiohydantoin. l4 /NHz R-CH 'C0,H

X

= 0. S,

R'N=C=X

X

R-CH

,NH-C, \

//

NHR'

CO,H

-HzO

R

X

H

(81

Se

\xR' (9)

Acid treatment of the substituted thioureas resulting from the treatment of esters, amides, or peptides of a-amino acids (10) with isothiocyanates (usually phenyl isothiocyanate) also affords 2-thiohydantoins (11). These reactions furnish the basis of the Edman's method for the stepwise degradation of peptides.'

R-CH

X

=

YNH2

\cox

PhNCS

,NHCSNHPh R-CH

\cox

H+

-R

\$:

+ HX

H

OR', NHR'

The rate constants for 3,Sdisubstituted 2-thiohydantoins prepared by Edman's procedure have been reported.' 3-Phenyl-2-thiohydantoins (PTH) P. Schlack and W.Kumpf, Hoppe-Seyler's Z. Physiol. Chem. 154, 125 (1926). H. Kubo, T. Nakajima, and Z. Tamura, Chem. Pharm. Bull. 19(1),210 (1971). I Z H. Fujiwara, A. K. Bose, M. S. Manhas, and J. M. Vander Veen, J.C.S. Perkin II,5,653 (1979). I' M. J. Korohoda, Pol. J . Chem. 54(4), 683 (1980). I4 J. H. Poupaert and G . Lhoest, Bull. Soc. Chim. Belg. 88(5), 339 (1979). I' V. Knoppova, J. Kovac, and I. Basnak, Collect. Czech. Commun. 39(3), 773 (1974). lo

IL

Sec. II.C]

181

HYDANTOINS

are obtained by cyclization of phenylthiocarbamoyl amino acids in an acetichydrochloric acid medium, following the Sjoquist modification of Edman's method.I6 This modification fails in the case of ~-azetidine-2-carboxylicacid and 14a is not obtained. However, the resultant phenylthiocarbamoyl derivative (I2a)with dicyclohexylcarbodiimide (DCC)gives 2-phenylimino-5thiazolidinone (13a) that thermally rearranges to racemic 14a. If the pnitrophenyl ester of 12a is used, then 14a is obtained with retained optical activity." In the 0x0 series, only the last procedure through the p-nitrophenyl ester gives 14b.

--w

I c=x I

X )fN\Ph

NHPh

a X=S

bX=O

Amino acids with protected side chains have also been characterized as phenylthiohydantoins by reaction with phenyl isothiocyanate. This procedure has been applied to monitor solid-phase peptide synthesis." Bridgehead nitrogen hydantoins have been obtained from imidazole-, pyrrolidine-, and piperidine-2-carboxylates,' as well as spirohydantoins, such as 15, derived from the aminolysis products of isatincarboxamides." Amino nitriles react in a similar manner.'~3*21*22 0 C ;$H,C-N iH,

H (15) I6

J. Sjoquist, Ark. Kemi 11, 129 (1957). H. T. Nagasawa, P. S. Fraser, and J. A. Elberling, J . Org. Chem. 37(3), 516 (1972). G. Milhand, D.J.P.Raulais, P. C. Rivaille, B. Daguilhanes, and G .J. G . Lefevre, J . Chem. Res.

Synop. 1, I 1 (1978). L. Capuano, M. Welter, and R. Zander, Chem. Ber. 103(8), 2394 (1970). l o L. Capuano and K. Benz, Chem. Ber. 110(12), 3849 (1977). W. Oldfield and C. H. Cashin, J . Med. Chem. 8(2), 239 (1965). 2 2 U.Krueger and G . Zinner, Arch. Pharm. (Weinheim, Ger.) 311(1), 39 (1978).

I82

c. AVENDARO L ~ P E ZAND G . GONZALEZ

TRIGO

[Sec. 1I.D

Chlorosulfonyl isocyanate is uniquely useful for the formation of hydantoins from sterically hindered acid- and base-labile amino nitriles, e.g., the synthesis of optically active spirohydantoins such as the biologically active (4S)-2,3-dihydro-6-fluorospiro(4H-1-benzopyran-4,4‘-imidazolidine)2’,5‘-di0ne.~~ Condensation of a-amino esters, a primary amine, and diphenyl carbonate is the modification of choice for derivatives containing carboxyl or hydroxyl groups.24

D. AMINO ACIDSAND UREAS This reaction has been known since Ware’s report,’ giving excellent yields in the case of amino acetamides and acetates with n i t r ~ u r e a . ~ ’ The reaction of urea or phosgene with amino acids gives “C-labeled hydantoins with potential utility as radiopharmaceuticals.26 The a-halogen acids are often used in reactions with primary amines and ~ r e a , as ~ well ’ ~ as ~ in ~ cyclocondensations of chloroacetates and ureas. Some 3-(benzothiazol-2-yl)-2-thiohydantoins derivatives have been obtained by this fashion.29 Similarly N ‘-(4-arylthiazole-2’-yl)thioureas, prepared from 2-amino-4arylthiazoles with benzoyl thiocyanate and subsequent hydrolysis of the product with alkali, condense with monochloroacetic acid in pyridine to give 2-thioh~dantoins.~’ Other amino acid derivatives, such as a-hydroxy acids and cyanohydrins, also react with urea to give hydantoins,’ e.g., the synthesis of 544hydro~ypheny1)hydantoin.~ Urea, methylurea, and dimethylureas react with glyoxylic acid and its methyl ester to give a-substituted hydantoic acid derivatives (16) and substituted allantoic acid derivatives (17), which can be cyclized to 5substituted hydantoins (18). Although allantoin (18) formation from urea and R. Sarges, H. R. Howard, and P. R. Kelbaugh,J. Org. Chem.47.4081(1982). K. Iwata and S. Hara, J . Heterocycl. Chem. 15(7), 1231 (1978). 2 5 E. Schipper and E. Chinery, J . Org. Chem. 26,3597 (1961). 23 24

D. Roeda and G . Westera, Int. J . Appl. Radiat. Isot. 32(1 I), 843 (1981). 0. Kochkanyan. Yu. A. Israelyan, and A. N. Zaritovskii, Khim. Geterotsikl. Soedin. 1.87 (1978). S. lcli and L. D. Colebrook, J . Pure Appl. Sci. 9(l), 39 (1976). M. Behera, P. N. Dhal, and A. Nayak, J . Indian Chem. Soc. 52( 1 l), 1067 (1975). 30 P. N. Dhal, T. E. Achary, A. Nayak, and M. K. Rout, J . Indian Chem. SOC.SO( lo), 680 (1973). 3 1 T. Ohashi, S. Takahashi, T. Nagamachi, K. Yoneda, and H. Yamada, Agric. Biol. Chem. 45(4), 831 (1981).

26

” R.

’* ’’

Sec. II.E]

183

HYDANTOINS

glyoxylic acid was described in 1876,32 this reaction is particularly interesting because the reverse sequence 18 + 16 is part of the biological degradation of uric acid to urea and glyoxylic acid. Ho\

CHCOzH

I

HzNCONHZ ’ (H ,NCONH),CHCOz H

NHCONH,

- H,NCON H H

Syntheses of relatively stable adducts of ureas and glyoxylic acid have been reinvestigated. Very good yields of 5-hydroxy-, 5-methoxy-, and 5-isopropylthiohydantoins have been achieved.33 Some 1-aryl-substituted hydantoins have been synthesized by acidcatalyzed condensation of monosubstituted ureas and glyoxal with moderate yields.34

E.

a-DICARBONYL COMPOUNDS AND UREA

DERIVATIVES

5,5-Disubstituted hydantoins and 2-thiohydantoins, especially their 5 3 diary1 derivatives, have been prepared by means of a condensation that involves a rearrangement similar to that in which benzilic acid is formed from benzil.’.’ Examples include the synthesis of fluorinated hydantoin~,~’ spir~fluorene-,~~ and spiroa~enaphthylenehydantoins,~’ 2-thiohydan3C3.40 and 5,5-diphenylhydantoin-2,4,5-’ 1-Substituted biguanides (19) also react with benzil on heating in alcohol in the absence of any catalyst to give 2-substituted guanilydene-5,5diphenylhydantoins (20), whose formation involves an anionotropic migration of a phenyl N-Amidino-0-alkylisoureas and 1-aryl- or l-alkyl3-amidino-2-thioureas behave similarly.42 32 33

E. Grirnaux, Hebd. Seances C. R. Acad. Sci. 83,62 (1876). D. Ben-Ishai, J. Altrnan, and Z . Bernstein, Tetrahedron 33(10), 1191 (1977).

J. Nernatollahi, Z. Mehta, and J. Langstron, J. Pharm. Sci. 62(2), 340 (1973). C. Joshi, V.N. Pathak, and M. K. Goyal, J . Heterocycl. Chem. 18(8), 165 (1981). 36 W. R. Dunnavant, J . Org. Chem. 22,991 (1957). 37 P. A. Crooks, T. Deeks, and F. de Sirnone, Gazz. Chim. Ital. 107 (5-6), 353 (1977). H. C. Chiang and J. R. KO, Heterocycles 19,529 (1982). 39 H. P. Das and G. N. Mahapatra, Indian J . Chem. 18B(3),257 (1979). 40 J. A. Kepler, J. W. Lytle, and G. F. Taylor, J . Labelled Compd. 10(4),683 (1974). 41 M. Furukawa, Y. Fijimo, Y. Kojirna, and S . Hayashi, Chem. Pharm. Bull. 20, 521 (1972). 42 S. Hayashi, M. Furukawa, K. Matsuoka, T. Yoshida, Y. Kojima, and S. Ayashi, Chem. Pharm. Bull. 22( l), 1 ( 1974). 34

” K.

184

C. AVENDARO L6PEZ AND G. GONZALEZ TRIG0

X-C-NH-C-NH, NH ‘I

I1

NH

+

OCPh

I

OCPh

-

[SeC. I1.F

N-C-X

Ph H

X = NHR, OR

1,2-Cyclohexanedione specifically reacts with the guanidino group of arginine and arginyl residues of proteins in 0.2 M alkali to form hydantoin (211.43

F. BUCHERER-BERGS SYNTHESIS FROM CARBONYL COMPOUNDS The Bucherer-Bergs synthesis is of general application to carbonyl compounds, employing potassium cyanide and ammonium carbonate. Carbonyl derivatives such as semicarbazones, thiosemicarbazones, oximes, azines, phenylhydrazones, imidazolidines, and azomethines also are readily converted directly to the corresponding hydant0ins.4~The extent to which the reaction occurs appears unrelated to the hydrolytic stability of the starting material. The proposed mechanism is given in Scheme 1. ‘s4

R,

/C=NR’

R

HCN R\C/CN =

R/

\NHR,

NHJ

R\C/CN R”

‘NH,

5 -

..

..

H

H

SCHEME 1 43

K.Toi, E. Bynum, E. Norris, and H. A. Itano, J . Bid. Chem. 242(5), 1036 (1967). J. N. Coker, W.L. Kohlase, T.F. Martens, A. 0.Rogers, and G. G. Allan, J. Org. Chem. 27(9), 3201 (1962).

Sec. II.F]

185

HYDANTOINS

Substitution of (NH,),CO, by H2NCOSNH, (prepared from COS and alcoholic NH,) in the presence of NaCN gives 4-thiohydantoins. Preformed a-amino nitriles also give 4-thiohydantoins, employing carbonyl sulfide.,’ The Carrington modification, using carbon disulfide, ammonium chloride, and sodium cyanide, affords 2,4-dithiohydantoin~.~~ If preformed a-amino nitriles react with carbon disulfide, 2,4-dithiohydantoins are also obtained. 4,4-Dialkyl-5-iminothiazolidine-2-thiones are probably first formed and then isomerize by the mechanism shown in Scheme 2.3 HN

R\

,NH, C

R’

R

5 \c/ R‘/

‘CN

NH-CQSH

\J! “13

-RLLR’

H

N

SCHEME 2

The mechanism is supported by the observation that a-methylamino nitriles (22), which cannot isomerize by this mechanism, afford 4,4-dialkyl-S-imino-3methylthiazolidine-2-thiones (23), which on prolonged reaction are converted to 5-methyliminothiazolidine-2-thiones (24) and 5,5-dialkyl-2,4dithiohydantoins (25).,’ The apparent methyl transfer shown in this scheme takes place by the interchange of ammonia and m e t h ~ l a m i n e . ~ ~ Me

R \ C /NH I R” ‘CN

(22)

R Z L-

5R

I

R ~ L + & J s

H

I

Me

Me

(23)

(24)

(25)

When the Carrington modification is applied to some sterically hindered piperidones such as tropinone or pseudopelletierine, the corresponding 45

H. C. Carrington, C. H. Vasey, and W. S. Waring, J . Chem. Soc., 396 (1959). C. Carrington, J . Chem. Soc., 681 (1947). F. L. Chubb and J. T. Edward, Can. J . Chem. 59(18), 2724 (1981). J. Taillades and A. Commeyras, Tetrahedron 30,127,2493,3407 (1974).

“ H.

‘’ ‘*

186

C. AVENDARO L6PEZ AND G. GONZALEZ TRIG0

[SeC. 1I.F

thiocyanates (26) are the main reaction produ~ts.~’ During the BuchererBergs reaction, ester groups are ~ a p o n i f i e d . ~ ~

n=0,1

The Bucherer-Bergs synthesis has been successfully applied to a great variety of cyclic ketones, ranging from cyclopropanone to steroidal ketones. However, the difficulty of preparing small-ring ketones has led to the development of alternative methods to obtain the corresponding spirohydantoins. Isocyanate intermediate 27 may be prepared in several steps from malonic ester; typical Bucherer-Bergs chemistry follow^.^'

X

= Br, H n=0.1

The synthesisof 5-(phenyl-’3C,)-5-phenylhydantoinis valuable in biomedical research.52The Bucherer-Bergs reaction is recognized to be suitable for characterization of 3-0xoalkyIpyrroles~~ as well as 1-(2-f~ryl)-2-alkanones.’~ A kinetic study of the Bucherer-Bergs synthesis of p-hydroxy-5phenylhydantoin has been rep~rted.’~ G. G. Trigo, C. Avendafio, and E. Santos, An. Quim. 75(9-lo), 761 (1979). P. Ballesteros, and A. Sastre, J. Heterocycl. Chem. 17(1). 103 (1980). ” W. Dvonch, H. Fletcher, and H. E. Alburn, J . Org. Chem. 29(9),2764 (1964). ” J. H. Poupaert, M. Winand, and P. Dumont, J. Labelled Compd. Radiopharm. 18,1827 (1981). ’3 A. Treibs, R. Wilhelm, and E. Herrmann, Liebigs Ann. Chem. 5,849 (1981). s4 E. H. Sund and D. S. Hunter, J . Heterocycl. Chem. 11(6), 1123 (1974). 5 5 A. P. Khardin, A. Gutmanis, A. I. Val’dman, B. I. Panfilov, D. I. Val’dman, S. Yu Sizoo, L. V. Semenova, 1. Leucbergs, A. Ozoes, and M. Dziena, Latv. PSR Zinat. Akad. Vestis, Kim. Ser. 4, 430(1981).

49

” G. G. Trigo, C. Avendafio,

Sec. II.F]

187

HYDANTOINS

Finally, yields from the Bucherer-Bergs reaction have been improved by several optimization procedure^.^^*^'

Stereochemistry of the Bucherer-Bergs and Read Reactions When the Bucherer-Bergs and Read methods are applied to some substituted cyclanones, two different epimeric products, designated a and 8, are found. After a long-standing controversy about the configurations of the hydantoins and their corresponding amino acids derived by hydrolysis,45.46.5 8-63 a mechanism proposed by Edward gives a coherent explanat i ~ nThe . ~ key ~ to the problem is that the Bucherer-Bergs reaction is under thermodynamic control, whereas Read’s is kinetically controlled. Edward concludes that the main epimer obtained by the Bucherer-Bergs procedure (a) has the C-4 carbonyl group in the less-hindered position, while the Read procedure yields the spirohydantoin of the opposite configuration ( p epimer). The modification of the Bucherer-Bergs reaction, using COS or CS2 to obtain 4-thio- or 2,4-dithiohydantoins, gives fl (with the C-4 thiocarbonyl group in the more crowded position). Finally, the use of thiocyanate instead of cyanate in the Read method yields 2-thiohydantoins with the p configuration (C-4 carbonyl group in the more crowded position).

(29)

(28)

(297

The mechanistic considerations are based mainly on the fact that amino nitriles 29 and 2 9 rapidly equilibrate in alkaline solution through the intermediacy of imine 28 but not in acid solution. The Read reaction is conducted under acidic conditions so that the in’terconversionof 2 9 to (29) is s6 F.

L. Chubb, J. T. Edward, and S. Ch. Wong, J . Org. Chem. 45(12),2315 (1980). C. Pedregal, G . G. Trigo, M. Espada, D. Mathieu, R. Phan Tan Luu, C. Barcel6, J. Lamarca, and J. Elguero, J . Heterocycl. Chem. 21,1527 (1984). H. L. Hoyer, Chem. Ber. 83,491 (1950). H. C. Brimelow and C. H. Vasey, British Patent 807,678(1959)[CA 53, 12303 (1959)J 6o L. Munday, J . Chem. Soc., 4372 (1961). H. C. Brimelow, H. C. Carrington, C. H. Vasey, and W. S. Waring, J . Chem. SOC.,2789 (1962). 62 R. J. Cremlyn and M. Chisholm, J . Chem. Soc. C, 2269 (1967). 63 Y. Maki and T. Masugi, Chem. Pharm. Bull. 21,685 (1973). 64 J. T. Edward and C. Jitrangsri, Can. J . Chem. 53,3339 (1975). s7

’* ’’

188

C. AVENDAfiO L 6 P E Z A N D G. GONZALEZ TRIG0

[SeC.

1I.F

prevented. The amino nitrile (mostly 29)reacts with cyanic acid to form a urea (30), which can then cyclize to /3-hydantoin (31'). N

On the other hand, the same amino nitrile treated with carbon dioxide in aqueous ethanol gives the a-hydantoin (31). The elaborated Edward's mechanism (shown only for the /I-series in Scheme 3) assumes the rapid interconversion 29 S 29 and that the rate-determining step in the path to 31' is 29a + 29b.The path leading to the a compound should be less favored in its earlier, preequilibrium steps, but the overall energy barrier must be lower for steric reasons.

(29'a)

(29'b)

(29'c)

SCHEME 3

Sec. II.F]

189

HYDANTOINS

When the carbon dioxide is replaced by carbon disulfide, the reaction takes the p path because the much greater nucleophilicity of the sulfur atom makes the reaction 29a + 29b exothermic and, therefore, its transition step should resemble 29a rather than 29b. Consequently, the steric barrier impeding the path to the hydantoin is missing on the fi path to the 2,4-dithiohydantoin, whereas the various steric factors impeding the a path are still present. The observation that, when carbon dioxide is replaced by carbon oxysulfide, the p- rather than the a-4-thiohydantoin is obtained, can be explained by similar reasoning. The reaction in the presence of CO, and a primary amine, in place of ammonium carbonate, gives 32 instead of the expected derivative (33)because the Bucherer-Bergs reaction requires N-unsubstituted a-amino nitriles, able to give the isocyanate intermediate 2 9 ’ ~ ~ ~

(32)

(33)

Kinetic and thermodynamic studies66 show the stability of the a-amino nitrile carbamate 29a versus pH to be determined mainly by the concentration of dissolved CO, and by the equilibrated formation of products from degradation of the a-amino nitrile, i.e., the amino dinitrile and the cyanoh ydrin. Among many studies which confirm the Edward’s rule is that dealing with tropane-3-spiro-5‘-hydantoins 34-36 in Scheme 4.49s67 N-Alkylgranatanine-3-spiro-5’-hydantoinsobtained by the BuchererBergs methods have the a-c~nfiguration.~*-~~ The stereoselectivity of the Bucherer-Bergs and Read reactions of bicyclo[3.2.1]0ctan-3-one~~ and Nmethyl-l0-azabicyclo[4.3.l]decan-8-one (homogranatanine) has also been ” G. G. Trigo, C. Avendafio, and

F. Marti, An. Quim. 73(3), 426 (1977). A. Rousset, M. Lasperas, J. Taillades, and A. Commeyras, Tetrahedron 36( 18), 2649 (1980). 6 7 G. G. Trigo, C. Avendafio, E. Santos, J. T. Edward, and S. Ch. Wong, Can. J . Chem. 57(12), 1456 (1979). 6 8 F. Florencio, P. Smith-Verdier, and S. Garcia-Blanco,Acta Crystallogr., Sect. B B34(4), 1317 (1978). 69 F. Florencio, P. Smith-Verdier, and S. Garcia-Blanco, Acta Crystallogr., Sect. B B34(7), 2220 (1978). 7 0 F. Florencio, P. Smith-Verdier, and S. Garcia-Blanco,Cryst. Struct. Commun. 9(3), 687 (1980). 7 1 G. G. Trigo, C. Avendafio, P. Ballesteros,and A. Gonzalez,J . Heterocycl. Chem. IS,833 (1978). 7 2 H. N. Christensen, M. E. Handlogten, J. V. Vagdama, E. de la Cuesta, P. Ballesteros, G. G. Trigo, and C. Avendafio, J . Med. Chem. 26, 1374 (1983). 66

190

[SeC. 1I.F

C. AVENDARO LOPEZ AND G. GONZALEZ TRIG0

KCN

(35). P

I 0

CICHzCOzH

CH 3

I

0

H

NH

SCHEME 4

confirmed.73 Other azabicyclo ketones have also been In all cases the configuration of the hydantoins agrees with the stereochemical predictions based on the Edward mechanism and in some cases with the stereochemistry of other reactions, such as reduction79 and the addition of organometallic reagents to carbonyl groups.80 The results of the Bucherer-Bergs and Read reactions on cyclopentanones such as cis-bicyclo[3.3.0]octan-3-one and cis-3,4-dimethylcyclopentanone show a stereochemical course related to the preferred conformation of the cyclopentane rings6’ The stereochemical preferences of biased cyclopentanones are much less pronounced than those of biased cyclohexanones, but Edward’s rule indicates trends. G. G. Trigo, E. Martinez, and E. Llama-Hurtado, J. Heterocycl. Chem. (in press). G. G. Trigo, E. Galvez, M. Espada, and C. Bernal, J. Heterocycl. Chem. 16,977 (1979). ’5 P. Smith-Verdier, F. Florencio, and S.Garcia-Blanco, Acta Crystallogr., Sect. B B35(8), 191 1 (1979). ’ 6 F. Florencio, P. Smith-Verdier, and S. Garcia-Blanco, Acta Crystallogr.,Sect. B B35(lo), 2422 (1979). 7 7 G. G. Trigo, E. Galvez, and C. Avendafio, J. Heterocycl. Chem. IS,907 (1978). 7 8 E. Martinez, C. de! Campo, and G. G. Trigo, Helu. Chim. Acta 66,338 (1983). ” H. 0.House, H. C. Muller, C. G. Pitt, and P. P. Wickham, J. Org. Chem. 28,2407 (1963). 8o H. 0 House and W. H. Bryant, J. Org. Chem. 30,3634 (1965). ’3

74

Sec. II.G]

HYDANTOINS

191

Other rigid cyclopentanones thus far studied have been (+)-camphor and ( ))-norcamphor. The stereochemistry of the reactions confirms Edward's rule. While ( &)-norcamphor gives, by the Bucherer-Bergs method, the

hydantoin with the C-4 carbonyl group in the exo position," (&)-camphor gives the hydantoin with an endo C-4 carbonyl group.82 These are, respectively, the more accessible

G. CONVERSION OF OTHER HETEROCYCLIC COMPOUNDS TO HYDANTOINS Hydantoins have been prepared from cyclic derivatives of urea by mechanisms that are not very reliable in most cases.' Some new ring transformations have clarified some mechanistic aspects, however.

1. Pyrimidine Rearrangement Ring Contraction

(37) with Reaction of several 5-bromo-3-alkyl-6-methyl-l-aryluracils monoalkylamines causes ring contraction to give hydantoin derivatives

Ar

H. S. Tager and H. N. Christensen, J . Am. Chem. SOC.94,968 (1972). Y. Maki, T. Masugi, and K. Ozeki, Chem. Pharm. Bull. 21(1I), 2466 (1973). 83 H.C. Brown, Chem. Br. 2, 199(1966). E. L. Eliel, in "Stereochemistry of Carbon Compounds," p. 303. McGraw-Hill, New York, 1962.

82

192

C. AVENDAfiO L6PEZ AND G. CONZALEZ TRIG0

[SeC. 1I.G

besides the normal substitution products. A reasonable reaction mechanism implies that intermediate 38 tautomerizes and hydrolyzes to give 39.85 Treatment of 5-acetoxy-6-(acetoxymethyl)uracils(40)with very dilute sodium hydroxide solution affords hydantoins (42) via the exocyclic

-

-

-

on -

on -

0

I

R'

-

I

R'

I

R'

R' (42)

N ',N 'o-Dialkylisoalloxazines react with molecular oxygen to give 4ahydroperoxides (43a), which provide, on spontaneous decomposition, 4apseudobases (43b). These intermediates undergo ring contraction in basic medium to yield spirohydantoins (44)" R' R' R' Et

Et

(439) R4 = OOH (43b) R4 = OH

The autooxidation of 1,3,5,6,7-pentamethyI-5~6,7,8-tetrahydroIumazine also yields spirohydantoins identified by X-ray analysis." Early results Sh. Senda, K. Hiroka, and K. Banno, Tetrahedron Lett. 35,3087 (1974). B. A. Otter, 1. M. Sasson, and R. P. Gagnier, J. Org. Chem. 47(3), 508 (1982). M. Iwata, T. C. Bruice, H. L.Carrell, and J. P. Glusker, J. Am. Chem. SOC.102(15), 5036(1980). ** H. Van Koningsveld, Tetrahedron 32(17), 2121 (1976). .s'

86

Sec. II.G]

193

HYDANTOINS

concerning the rearrangement of uric acid and its derivatives probably involve a similar mechanism.' Hydrolysis of isoalloxazines (flavins, 45) generally occurs via nucleophilic addition of OH- to the l0a-position to provide hydantoins (46),which by intramolecular dehydration in acidic medium give 45.89*90

I

R'

R'

(45)

(4)

Spirohydantoins have also been found to result from reactions of several nucleophiles with 1,3,1O-trimethylflavinium per~hlorate.~' In the same context is described the pyrimidine ring contraction of the flavinium cation 47 with OH- through the 4a-adduct 48 or its isomer 10a-adduct 49 to the spirohydantoins 50 and 51.92 Me

R

Et

R

(47)

(48) R = M e , R = E t (49) R = Et, R = Me

Me Me

OH 0

(So) R = M e , R = E t (51) R = Et, R = Me

T. C. Bruice, T. W. Chan, J. P. Taulane, I. Yokoc, D. L. Elliot, R. F. Williams, and M. Novak, J . Am. Chem. Soc. 99(20),6713 (1977).

F. Yoneda, Y. Sakuma, and K. Shinozuka, J.C.S. Chem. Commun. 6,175 (1977). K. H. Dudley and P. Hemmerich, J . Org. Chem. 32(10), 3049 (1967). 92 H. I. Mager, Tetrahedron Lett. 37, 3549 (1979).

194

C. AVENDARO L6PEZ AND G . GONZALEZ TRIG0

[SeC. 1I.H

Some pyrimidine derivatives, such as alloxan, react in the absence of mineral acid with 3,4-diaminopyridinesto give hydantoins through a ureideg3 in analogy to the cyclization of 1,4,5-triazanaphthaIenecarboxy~reides.'~

2. From Other Heterocyclic Compounds 4-Arylmethylene-2-benzylthio-2-thiazolin-5-onesform 3-aryl-5-arylmethylene-2-thiohydantoinsby treatment with ammonia or primary aromatic amines in acetic acid.9s*96 The mechanism probably involves, in a first stage, ring opening of the thiazolone ring at C-5. Treatment with diborane of the bicyclic hydantoin derivative 2,3-dihydro-6,6-diphenylimidazo(2,l-b)oxazol5(6H)-one9' gives 5,5-diphenyl-3-ethylhydant0in.~~

H. CYCLOADDITION REACTIONS WITH HETEROCUMULENES 1. Reaction with 3-Dimethylamino-2H-azirines Azirine 52 (Scheme 5 ) reacts with carbon disulfide and isothiocyanates with splitting of the azirine N-l=C-3 double bond to give dipolar five-membered heterocyclic 1:l adducts. In some cases, these products can undergo secondary reactions to yield 1:2 and 1:3 adducts. Hydrolysis of the adducts formed with isothiocyanates affords thioureas, which easily cyclize to yield 2-thiohydantoins (53).99 Amines trap the adducts with carbon disulfide and give dithiohydantoins (54)with thiourea intermediates.loOSimilarly, hydrolysis of the 1:1, 1:2, and 1:3 adducts with isocyanates yields hydantoins (55)."' With arylsulfonyl isocyanates, the adducts lead to amidines, which readily rearrange with a shift of the sulfonyl group to give imidazolinones,which afford 1arylsulfonylhydantoins(56).'02 Some 2-monosubstituted azirines, also afford hydantoins by treatment with aryl isocyanates and subsequent hydrolysis.'03 J. W. Clark-Lewis and R. P.Singh, J . Chem. SOC.,3162 (1962). J. W. Clark-Lewis and M. 3. Thompson, J. Chem. SOC.,430 (1957). " A. M. Khalil, I. I. Abd El-Gawad, and M. Hammouda, Aust. J . Chem. 27(9), 2035 (1974). 96 A. H. Harhash. M. H.Elnagdi, and Ch. A. S. Elsannib, J . Prakt. Chem. 315(2), 211 (1973). 97 V. E. Marquez, L.Twanmoh, H.B. Wood, and J. S. Driscoll, J . Org. Chem. 37,2558 (1972). 98 V. E. Marquez, T. Hirata, L. Twanmoh, B. Harty, and J. S. Driscoll, J . Heterocycl. Chem. 9(5), 93 94

1145 (1972). 99

loo

lo)

E. Schaumann. E. Kausch, and W.Walter, Chem. Ber. 110,820 (1977). E. Schaumann. E. Kausch, S. Grabley, and H. Behr, Chem. Ber. 111(4), 1486 (1978). G . Mukherjee-Muller, H. Heimgartner. and H. Schmid, Helo. Chim. Acra 62(5), 1429 (1979). E. Schaumann and S. Grabley, Chem. Ber. 113,934 (1980). E. Schaumann, S. Grabley, and G. Adiwidjaja, Liebigs Ann. Chem. 2,264 (1981).

(sr)x = 0,S, NR' Me NMe,

R

(52)

Me>$ Me

N H

X

Me

I RZ

(54) = s (58) X = s e

x

(55) R 2 = H, CONHR, CONRCONHR (56) R 2 = S0,Ar; R' = H SCHEME 5

196

[Sec. I1.H

C. AVENDAfiO L6PEZ AND G. GONZALEZ TRIG0

Some carbodiimide adducts with 52 give, by hydrolysis, thiolysis, or aminolysis, 24minohydantoins, 2-imino-4-thiohydantoins and 2,4-diiminohydantoins, respectively (57).'03 The carbon diselenide adducts afford 2,4-diselenohydantoins (58) with arnine~."~ Dipolar adducts, formed by the mechanism shown in Scheme 6, have been proposed to explain the unusual hydrolysis of the a-thiocarbamoylsubstituted carbodiimide 59 to a thiourea, which then eliminates dimethylamine and closes to form the 2-thiohydantoin (60).los

SCHEME 6

;Me,

NMe,

CS-NH-CH(CH3),

I

Me C=O MeXNH

I

NMe,

-

CH(CH,),

0 M e x Me N H

C

(60)

Diazomethylcarbonyl compounds react similarly with tosyl isocyanate to give hydantoin derivatives.lo6 E. Schaumann, H. Nimmesgern, C. Adiwidjaja, and L. Carlsen, Chem. Ber. 115,2516 (1982). E. Schaumann, E. Kausch, K.H. Klaska, and B. Metz, Naturwissenschafren @(lo), 528 (1977). ' 0 6 M. Regitz, B. Weber, and A. Heydt, Liebigs Ann. Chem. 2,305 (1980). lo4 lo'

Sec. II.H]

197

HY DANTOINS

2. Reaction with Nucleophilic Carbenoids or Ylides Nucleophilic carbenoids (also called ylides by some authors) react with heterocumulenes, such as isocyanates and isothiocyanates, to yield hydantoins, 2-thiohydantoins, and 2,4-dithiohydantoins via dipolar intermediates. Thus dimethoxycarbene adds to aryl isocyanates and isothiocyanates to form 5,5-dimethoxyhydantoins and dithiohydant~ins.'~' Thiazolium ylides (61) (resultingfrom thiazolium salts and NEt, in DMF) give dipolar 1:l adducts (62) or 1:2-cycloadducts (63)with isocyanates or isothiocyanates."'-' lo Other substrates are imidazolidine" or 2-imidazoline derivatives.

'

''

R1

X

1:)--(!!-NR4

R2

- 1;) -R1

R j & i '

R2

I

I

R

R3 62)

(61)

R2

X

I ~3

1 R4

(63)

A related reaction uses cyclic peraminoethylenes, particularly A2*2'-bis( 1,3disubstituted imidazolidines)(64), as starting materials. These powerful bases are extremely reactive and, in the presence of isocyanates or isothiocyanates, yield inner salts (65)with a 1,3-dipolarstructure, which undergo cycloaddition with suitable dipolarophiles, such as isocyanates or isothiocyanates, to give the corresponding spirohydantoins. In many cases the spiro derivative is obtained in one step."'

[:)=(:]R

I

R

I

R

+ PhNCX

I

R

I

R

R

R. W. Hoffmann, K. Steinbach, and B. Dittrich, Chem. Ber. 106(7), 2174 (1973). A. Takamizawa, K. Hirai, and S. Matsumoto, Tetrahedron Lett. 37,4027 (1968). J. Hocker and R. Merten, Liebigs Ann. Chem. 751,145 (1971). A. Takarnizawa, S. Matsumoto, and Sh. Sakai, Chem. Pharm. Bull. 22(2), 293 (1974). 1 1 1 R. W. Hoffmann, B. Hagenbruch, and D. M. Smith, Chem. Ber. 110(1), 23 (1977). H. Giesecke and J. Hocker, Synthesis 11,806 (1977). H. E. Winberg and D. D. Coffman, 1.Am. Chem. SOC.87,2776 (1965). lo'

198

C. AVENDARO L6PEZ AND G. GONZALEZ TRIG0

[SeC. 11.1

3 . Reaction with I-Oxa-4-aza- and I ,4-Diazabutadienes 1-Oxa-4-azabutadienes and l,.l-diazabutadienes give, on reaction with heterocumulenes in 1,3-cycloaddition reactions, various 5,5-disubstituted derivatives of 1,3-diarylhydantoins(a).' 14*' Relatively high yields, mild conditions, and a very weak effect of solvent polarity on the reaction rate suggest a synchronous mechanism involving 1,Zmigration of a substituent.

''

'0

Ar'

X =O,ArN R3 = COR. CONHAr

If R3 = CONHR and R4 = Ar, then heating the cycloaddition product above its melting point splits off aryl isocyanate and gives 1,3,5triarylhydantoin.

''

4. Reaction with Phenylacetylene In the reaction of phenyl isocyanate with phenylacetylene in the presence of Fe(CO)', 5-benzylidene-1,3-diphenylhydantoinwas obtained in 85% yield by an addition reaction and hydrogen shift.' ''I Other phenylacetylenes behave similarly.' *

'

I. MISCELLANEOUS METHODS STARTING FROM AMINO ACID DERIVATIVES OR RELATED SUBSTRATES As discussed in Sections I1,B-D, these starting materials have been applied with success to prepare hydantoins.' Recently,new and sophisticated methods have been developed to improve and expand the utility of amino acids. Thus,

'I6

'I7 'I8

J. Moskal, A. Moskal and P. Milart. Tetrahedron 38(12), 1787 (1982). J. Moskal, J. Bronowski, and A. Rogosvki, Monatsh. Chem. 112,1405 (1981). J. Moskal and A. Moskal, Synthesis 10,794(1979). I. Oshiro, K. Kinugasa, T. Minami, and T. Ogawa, J . Org. Chem. 35,2136(1970). A. Baba, Y.Ohshiro,and T. Agawa, J . Organomet. Chem. 87(2), 247 (1975).

Sec. 11.11

199

HY DANTOINS

N-( 1-benzotriazolylcarbonyl)amino acids are especially useful to prevent racemization.' A modification of the stepwise degradation of peptides involves their N-terminal cyclization with N,N'-carbonyl- or N,N'-thiocarbonyldiimidazole."' Acetylation of N-hydroxyphenylurethane (67) yields the diester 68, which by simply heating in refluxing ethanol furnishes the N-acetoxyhydantoin 69.'"

OCOCH (68)

(67)

(69)

Normal substitution products of potassium N-cyanoanilide and nitriles or esters yield hydantoins by acid hydrolysis. Hydrogen sulfide treatment of 70 gives 2-thiohydantoins in excellent yield.IZ2 Ph,CX

I

PhNC=N

X = CN, C0,Et

Racemic and optically active hydantoins have been prepared through isocyanate derivatives, starting from chiral disubstituted cyanoacetic acids 71.I2 Similarly, N ',N '-disubstitu ted thiocyanatocarboxylic h ydrazides give 3-amino-2-thiohydantoin derivatives 72,' 24 and 1-phenyl-3-aminohydantoin is obtained in excellent yield in the reaction of ethyl N-phenyl-Ncarbethoxyglycinateand hydrazine hydrate.'25 Isomerization of thiocyanatofumaric and -maleic esters affords a mixture of the corresponding isothiocyanate esters, which react with primary amines to give 2-thi0hydantoins."~ lZo

Iz4

Iz5 Iz6

B. Zorc and I. Butula, Croat. Chem. Acta 54,441 (1981). F. Esser and 0.Roos,Angew. Chem. 90(6), 495 (1978). S. C. Bell, G . Conklin, and R.J. McCaully, J . Heterocycl. Chem. 13(1), 51 (1976). G. Sirnig, K. Lernpert,and J. Tamas, Tetrahedron 29(22),3571 (1973). J. Knabe and W. Wunn, Arch. Pharm. (Weinheim, Ger.) 313(6), 538 (1980). H. Boehme, F. Martin, and J. Strahl, Arch. Pharm. (Weinheim, Ger.) 313(1), 10 (1980). B. T. Gillis and J. G . Dain, J . Heterocycl. Chem. 8(2), 339 (1971). P. C. Thierne and E. Haedicke, Liebigs Ann Chem. 2,227 (1978).

200

[SeC. 1I.J

C. AVENDARO LOPEZ AND G. GONZALEZ T R I G 0

R'xcN

RI

R2

RZXNHCONHR3

1

i. NPNJ

3. R'NHz,

C02H

CN

0 H

R'-CH,

R' 'CH-NH

/

,CNHN,

0"

/R2

KSCrN +

'R

1

C o4 \NH

\CO,R~

1

R2

The old method of reaction between urea and unsaturated acids' has been reported for the synthesis of 5-aroylmethylthiohydantoinsby reaction of fiaroylacrylic acids and thiourea.'*' N-Carbethoxyamino acid amides (73) easily cyclize in the presence of tetrabutylammonium fluoride to give substituted hydantoins in excellent yields.12* Mild aqueous alkaline treatment of peptides containing 2,2-dibenzyloxycarbonylamidopropionic acid as the N-terminal residue easily gives 5-amino5-methylhydantoins,which are not available from 5-halohydantoin~.'~~.' 30 Other urethanes react ~imilarly.'~' The 5-amino group reacts very easily with nucleophiles such as water to give 5-hydroxyhydantoins.' 32

J. OTHER METHODS 1. Condensation of Imines with Isonitriles and Thiocyanic Acid

4-Iminohydantoins have been prepared according to Scheme 7.'33*'34The hydrolysis of the alkylimino groups affords hydantoins and 2-thiohydantoins.

"'R. D. Khachikyan, S. M. Atashyan, and S. G. Agbalyan, Ann. Khim. Zh. 34(9), 775 (1981). J. Pless, J . Org. Chem. 39(17), 2644 (1974). E. J. McMullen, H. R. Henze, and B. W. Wyatt, J . Am. Chem. Soc. 76,5636 1954). 130 A. B. Evnim, A. Lam, and J. Blyskal, J. Org. Chem. 35,3097 (1970). 1 3 ' G. Zanotti and F. Pinnen, J . Heterocycl. Chem. 18, 1629 (1981). 1 3 2 G. Lucente and G. Zanotti, J . Heterocycl. Chem. 8(6), 1027 (1971). 1 3 3 1. Ugi, Angew. Chem. 74.9 (1962). ' 34 1. Ugi, K.Risendahll, and F. Bodesheim, Justus Liebigs Ann. Chem. 666,54 1963).

12'

Sec. II.K]

HYDANTOINS

20 1

SCHEME I

2. Reaction of N-Cyanoamines with Z-tert-Butyl-3,3dipheny lazir idinone The reaction of N-cyanoamines with 1-tert-butyl-3,3-diphenylaziridinones is a general method for the synthesis of 1-alkyl-, 1-aralkyl-, and l-aryl-5,5diphenylhydantoins and glycocyamidines and is a new approach for the synthesis of hydantoins in which the aziridinone ring constitutes the C-5C-4-N-3 unit of the hydantoin ring and the cyano amine the N-1-C-2 unit.' 35 In a similar reaction scheme, a-chloro-a,a-diphenylacetamidesand potassium N-cyanoanilide give hydantoins.' 36

K. MUTUALTRANSFORMATIONS BETWEEN HYDANTOINS AND THIOHYDANTOINS Most 5,5-disubstituted hydantoins (74) give 5,5-disubstituted 2,4-dithiohydantoins (75) by reaction with phosphorus tri~ulfide'~'or pentasulfide13* (Scheme 8). 5,5-Disubstituted2,4-dithiohydantoins (75) react with ammonia or amines preferentially at the 4-position to give imino derivatives (76) which can be hydrolyzed by acid to 2-thiohydantoins (77). C a r r i n g t ~ nfound ~ ~ ethanolamine convenient for this purpose. Acid hydrolysis of the methylthio 13'

13' 13*

G . Simig, K. Lempert, J. Tamas, and G. Czira, Tetrahedron 31(9), 1195 (1975). G . Simig and K. Lempert, Tetrahedron 31,983 (1975). H. R. Henze and P. E. Smith, J . Am. Chem. SOC.65,1090 (1943). H. C. Carrington and W. S. Waring, J . Chem. SOC.,354 (1950).

202

[SeC.

C. AVENDARO L6PEZ AND G . GONZALEZ TRIG0

.-

1I.K

..

H

H

(74)

(75)

I

MeiSO,

SMe

H,Ot

I ..

HJO

+

..

H

H

(79)

SCHEME 8

derivatives(78)obtained by methylation of the 2,4-dithiohydantoins affords 4thiohydantoins (79). Boiling 20% aqueous chloroacetic acid completely removes the sulfur from 2,4-dithiohydantoins to give hydantoin derivatives. In some compounds, such as 80, the reaction with phosphorus pentasulfide gives bicyclic derivatives (81).’39

-

NH I H,C’

139

co

I

Me

Me H3C--(NI$=S S N

I

Rrl 0

R‘

-

N

H

Me

Z. 1. Moskalenko and G . P. Shumelyak, Khim. GeterosikL Soedin. 7,932 (1974).

Sec. III.A]

203

HY DANTOINS

III. Physicochemical Studies on Hydantoins 'H-NMR, IR, and UV techniques have been used to study ionization and tautomerism in h ~ d a n t 0 i n s . l ~ ~

A. IONIZATION Hydantoins are weak acids which owe their acidic character to dissociation of the proton bonded to the 3-nitrogen atom since this allows for maximum delocalization of charge in anion 82.' For unsaturated hydantoin derivatives, such as 5-arylidene-or 5-ethoxycarbonylmethylidenehydantoins,IR, UV,and NMR data show that the N-3-substituted derivatives lose the proton from the 1-nitrogen atom in alkaline solution, forming an anion which can delocalize through the 5-~ubstituent.'~'*'~~ Because the thiocarbonyl group is more strongly electron attracting than the carbonyl, 2-thiohydantoin (pK, 8.5)3 is a slightly stronger acid than hydantoin (pK, 9.12).'43*'444-Thiohydantoins appear to be weaker acids than 2-thiohydantoins,' and 2,4-dithiohydantoins are s t r ~ n g e r . ' ~ ~ . ' ~ ~ Ionization constants are affected only to a minor extent by alkyl substitution at the 1- and 5-positions, although some N-1 substituents greatly affect the pK, values. For instance, 1-benzenesulfonylphenytoinhas pK, 4.89, while phenytoin has a pK, value of 8.31.14' 3-Substituted hydantoins show no measurable acidity in aqueous alkali,'48 and 3-substituted 2-thiohydantoins are very weak acids (pK, ll).14' Reported pK, values of hydantoins have covered a relatively narrow range of acid strengths (pK, 8.33-9.19).'43*'44*'50Remarkably low pK, values (7-7.5) have been found for granataninespirohydantoins.'

-

'

B. I. Ivin, G. V. Rutkovskii,N. A. Smorygo,A. I. Dyachkov,G. M. Frolova, apd E. G. Sochilin, Zh. Org. Khim. 9(11), 2405 (1973). 141 B. A. Ivin, G. V. Rutkovskii, N.A. Smorygo, and E. G. Sochilin, Zh. Org. Khim. 6(12), 2601 ( 1970). 142 G.V. Rutkovskii, B. A. Ivin, V. A. Kirillova, N. A. Smorygo, and E. G. Sochilin, Zh. Obshch. Khim. 40(7), 1583 (1970). M. Zief and J. T. Edsall, J. Am. Chem. Soc. 59,2245 (1937). L. W.Pickety and M. McLean, J . Am. Chem. Soc. 61,423 (1939). J. T. Edward and 0.J. Chin, Can. J. Chem. 41,1650 (1963). '41 E. Santos, I. Rosillo, B. del Castillo, and C. Avendafio, J. Chem. Res., Synop., 131 (1982). 14' H. Fujioka and T. Tari, J. Pharm. Dyn. 5,475 (1982). lA8 R. E. Stuckey, J. Chem. SOC., 331 (1947). 149 J. T.Edward and S. Nielsen, J. Chem. SOC.,5075 (1957). S. P. Agarwal and M. I. Blake, J. Pharm. Sci. 57, 1434 (1968). E. Santos, C. Avendafio. I. Rosillo, and G. G.Trigo, J. Perkin 11, 389 (1982). I4O

204

C. AVENDARO LdPEZ AND G. GONZALEZ TRIG0

[SeC.

I1I.c

B. ULTRAVIOLET SPECTROSCOPY

'

The ultraviolet absorptions of thioamides have been studied by Janssen. " The band of low intensity and at the longest wavelength (Band I) that is assigned with reasonable certainty to n -P II*transitions of the thiocarbonyl group often appears as a shoulder or inflection of the slope of the more intense type I1 bands at shorter wavelengths. These bands have been assigned to n -+ o* transitions of the thiocarbonyl group. UV spectra have proved that potentially tautomeric thiohydantoins have thione and not mercapto structures, since their spectra are profoundly affected by S-methylation and only slightly by N-rnethylati~n.'~~*'~' Ionization of 2-thiohydantoins in alkaline solution leads to characteristic changes in absorption. It results in a slight hypsochromic shift but a big increase in intensity of the main peak, and a hypsochromic shift and decrease in intensity of the subsidiary peak. Several pK, values of thiohydantoins have been determined by s p e c t r o p h ~ t o m e t r y . ' ~54 ~~~~~*~~~*~ The pK, value for 5,5-diphenylhydantoin has also been determined by spectrophotometric measurement^,'^^ although weak optical absorption values have been found for other h ~ d a n t 0 i n s . l ~ ~

C. MASSSPECTROMETRY The mass spectral decomposition of hydantoin derivativescontaining alkyl and phenyl substituents have been investigated, using labeling techniques. The mass spectra of h y d a n t ~ i n , ' ~ t h~i ~ h y d a n t o i n s , ' ~ ~ 5-substituted -'~~ hyd a n t o i n ~ , ' ~ ~ * ' and ~ ~ -3-arylhydantoin~'~~ '~' have shown that cleavage of the hydantoin ring occurs by a-fission at the C-4 carbonyl group with loss of CO and RNCO. Aryl isocyanate ion formation occurs through several pathways, and the substituent effects on its formation obey the Hammett e q ~ a t i 0 n . l ~ ~ M. J. Janssen, Red. Trau. Chim. Pays-Bas 79,454 (1960). J. T. Edward and J:K. Liu, Can. J . Chem. 50,2423 (1972). J. T. Edward and J. K. Liu, Can. J . Chem. 47, 1117 (1969). R. A. Corral, 0.0.Orad, A. M. Duffield, and C. Djerassi, Org. Mass Spectrom. 5,551 (1971). 'sI R. E. Ardrey and A. Darbre, J. Chromatogr. 87.499 (1973). T. Sizuki, K. D. Song, and K. Tudmura, Org. Mass Spectrom. 11.557 (1976). 158 T. Suzuki, S. Matsui, and K. Tuzimura, Agric. Bid. Chem. 36, 1061 (1972). R. A. Locock and R. T. Coutts, Org. Mass Spectrom. 3,735 (1970). A. J. Atkinson, J. MacGee, J. Strong, D. Gartiez, and T. E. GatTney, Biochem. Pharmacol. 19, 152

Is3

"'

2483 (1970).

H. M. Fales, G. W.A. Milne, and N. C. Law, Arch. Mass Spectral Data 2(4), 650 (1971). G. Ruecker, P. N. Natarajan, and A. F. Fell, Arch. Pharm. (Weinheim, Ger.)304,833 (1971). B. M. Kwon and S.Ch. Kim, J . S . Perkin 11,761 (1983).

Sec. I I I . D ]

HYDANTOINS

205

The heterocyclic rings of 1,3,5-triarylhydantoins cleave via the aziridinone intermediates (83)with ejection of aryl isocyanate.The hydantoins containing substituents possessing carbonyl groups joined directly to the heterocyclic ring in position 5 reveal a great tendency to eliminate them under electron impact.'64

Ar

The mass spectra of 1,5,5- and 3,5,5-trisubstituted hydantoins have also been discussed. 2 2 ~ 1 6s Mass spectra have been used in the analysis of amino acid phenylthiohydantoin derivatives formed during Edman degradation of proteins.' 66 Gas chromatographic-mass spectrometric methods to detect and quantify very low levels of biologically active hydantoins have been deve10ped.I~~

'

"J

D.

INFRAREDSPECTROSCOPY

Hydantoins show two bands in the carbonyl region at about 1720 and 1780 cm-'.However, their interpretation has been the subject of controversy. The low-frequency band has been attributed both to the C-416* and the C-2 carbonyl group.' 69 Infrared and Raman spectra have also been interpreted in terms of carbonyl coupling similar to that found in imides.' 70 Other studies have confirmed this coupling." Many studies concerning the origin and localization of the characteristic IR frequencies of the CO and NH groups in hydantoins have been 164

J. Moskal, K. Nagraba, and A. Moskal, Org. Mass Spectrom. 15(5), 257(1980).

"'K. Lempert, K. Zaer, J. Mqiller, and G. Schroll, Acta Chem. Scand. 26, 1542 (1972). H. M. Fales, Y. Nagai, G. W. A. Milne, H. B. Brewer, T. Brouzert, and J. J. Pisano, Anal. Biochem. 43(1), 288 (1971). 16' J. Plowman, D. 8. Lakings, E. S. Owens, and R. H. Adamson, Pharmacology 15(4), 359 (1977). 16' J. Derkosch, Monatsh. Chem. 92,361 (1961). 169 P. S. A. Demoen, Bull. SOC.Chim. Belg. 75,524 (1966). Ch. Fayat and A. Foucaud, Bull. SOC.Chim. Fr. 3,987 (1971). ''I J. Bellanato, C. Avendafio, P. Ballesteros, and M. Martinez, Spectrochim. Acta, Part A 35A, 807 ( 1 979). 166

206

c.AVENDAROL ~ P E ZAND G. GONZALEZ

TRIGO

[Sec. 1II.E

reported.’ 72-’74 In 2-thiohydantoins, strong coupling occurs between C-S and C-N vibration, resulting in numerous bands in the 1550-1200 cm-’ r e g i ~ n . ’ ~ ’ . ’The ~ ~ identification in the literature is often based on the “thioureide band.”17’.’ 77 Antisymmetric stretching modes of NCS bonds complete the characteri~ation.”~ * 0 hydrogen bonds, IR results have revealed in some Besides N-H granatanine- and nortropane-3-spiro-5’-hydantoinsother strong hydrogen bonds between the N-3-H group and the piperidine nitrogen atom.’7’ Some of these compounds exist as zwitterion structures in the solid state.’ 7 9 Infrared results also support the idea that hydrogen bonding is the main factor in the formation of molecular compounds between 5,5-disubstituted hydantoins and some pyrazolone derivatives such as antipyrine. 147 Urey-Bradley force constants have been calculated, using the vibrational frequencies of hydantoin or 2-thiohydantoin and its N-lJ-3-dideutero derivatives.’ ‘O.’

E. NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY ‘H-NMR spectroscopy is particularly useful for localization of substituents in the hydantoin ring, considering the chemical shifts of protons at 1,3- and 5positions and the characteristic changes of the N-1-H and N-3-H signals on addition of bases.lE2 From the NMR study of 5,5-diphenylhydantoin, its thioxo analogues, and their possible N- and S-methyl derivatives, correlations have been found between the chemical shifts of the resonance signals and the chemical structures of the compound^.'^^

”*

J. H. Elliot and P. N. Natarajan, J . Pharm. Pharmacol. 19,209 (1967). A. R. Katritzky and P. J. Taylor, in “Physical Methods in Heterocyclic Chemistry” (A. R. Katritzky, ed.), Vol. 4, p. 265. Academic Press, New York, 1971. S. Goenechea, Mikrochim. Acta 3,276 (1972). 1 7 ’ D. T. Elmore,J. Chem. Soc., 3489(1958). C. Cogrossi, Spectrochim. Acta, Part A 28A(S), 855 (1972). I ” K. A. Jenssen and P. H. Nielsen, Acta Chem. Scand. 20, 597 (1966). 17’ J. Poupaert and R. Bouche, J . Pharm. Sci. 65(8), 1258 (1976). 1 7 9 J. Bellanato, C. Avendailo, P. Ballesteros, E. Santos, and G . G. Trigo, Spectrochim. Acta, Part

“O

“I

Is’

A X A , 879 (1980). K. Geetharani and D. N. Sathyanarayana, Indian J . Pure Appl. Phys. 16(2), 88 (1978). Y. Saito and K. Machida, Bull. Chem. Sac. Jpn. 51(1), 108 (1978). R. A. Corral and 0.0.Orazi, Specfrochirn. Acta 21(12), 2119 (1965). P. Sohar, J. Nyitrai, K. Zaner, and K. Lempert, Acra Chim.Acad. Sci. Hung. 65(2), 189 (1970).

Sec. III.F]

HYDANTOINS

207

'H- and "C-NMR spectroscopy have helped to solve several configurational and conformational problems in h y d a n t o i n ~ ; ~ ' * ' ~ . ' ~ and " ' ~ ~the energy barrier for free rotation about the N-C bond in 3-aryl-2thiohydantoins has been calculated by 'H-NMR experiment^."^ Diastereomeric solute-solvent interactions of 1- and 3-arylhydantoins in chiral solvents have been studied.'" 'H- and I3C-NMR data have been reported for diagnostic purposes in direct analysis of phenylthiohydantoin amino acid derivatives (PTH)pro~ duced in the Edman degradation of peptides and p r ~ t e i n s . ' ' ~ - ' ~The insensitivity of 'H-NMR spectroscopy constitutes a major hurdle for its application in the sequence study of pep tide^.'^^.'^^ Alternatively, identification of the cleaved amino acids in the automated Edman degradatioii has been solved in some cases by using IR,196198 mass,'99 and gas chromatographic techniques.'"

F. CRYSTAL STRUCTURE DETERMINATIONS Most X-ray diffraction studies have been undertaken to confirm the structure of hydantoins and thiohydantoins or their derivatives obtained by Many others have emphasized conunusual rneth~ds.'~~~'~"'~'~~~~~~~'~~ G. G. Trigo, M. Martinez, and E. Galvez, J. Pharm. Sci. 70(1),87 (1981). L.D. Colebrook and M. A. Khadin, Org. Magn. Reson. 19(1),27 (1982). I. Attia and I. Z . Siemion, Rocz. Chem. 50(12),2063 (1976). ''' I. A. Attia, T. Glowiak, and 1. Z. Siemion, Bull. Acad. Pol. Sci. Chim. 24(10),781 (1976). L. D. Colebrook, S.Icli, and F. H. Hund, Can. J . Chem. 53(ll),1556 (1975). Is9 K.Izumi, Anal. Biochem. 85( l),306 (1978). ''O I. Z. Siemion, I. Attia, and K. Nowak, Bull. Akad. Pol. Sci.,Ser. Sci. Chim. 23(7), 575 (1975). 19' I. Z.Siemion, K. Sobczyk, and B. Picur, Pol. J. Chem. 52(3),667 (1978). K. Sobczyk and I. Z . Siemion, Pol. J. Chem. 54(9), 1833 (1980). ''' M.L. Bouguerra and Y.Leraux, C. R. Hebd. Seances Acad. Sci., Ser. C 273(16),991 (1971). 194 C. S.Tsai, N. L. Fraser, H.Avdovich, and J. P. Farrant, Can. J. Biochem. 53(9), 1005 (1975). T. Suzuki, T. Tomioka, and K. Tuzimura, Can. J. Biochem. 55(5),521 (1977). J. Ramachandran, Nature (London)206,927(1965). l'' C. Djerassi, K. Undheim, R. C. Sheppard, W.G. Terry, and B. Shoberg, Acta Chem. Scand. 15, 903 (1961). J. A. Poupaert, M. Claesen, J. Delegaen, and P. Dumont, Bull. Soc. Chim. Belg. 86(6), 465 (1977). '91 N. S.Vul'fson, V. M. Stepanov, V.A. Puchkov, and A. M. Zyakun, Iz. Akad. Nauk SSRR, Ser. Khim. 8,1524 (1963). H. Tschesche, R. Obermeier, and S.Kupfer, Angew. Chem., Int. Ed. Engl. 9(1l),893 (1970). T. Kinoshita, S.Sato, and Ch. Tamura, Tetrahedron Lett. 40,3695 (1971). '02 A. F.Cameron, I. R.Cameron, and F. D. Cuncanson, J.C.S. Perkin I1 5,789(1981). Is'

'"

208

C. AVENDAfiO LOPEZ AND G. GONZALEZ TRIG0

[SeC. 1II.F

figurational and conformational s t ~ d i e s , ' ~ ~especially -'~~ those of GarciaBlanco and C O - W ~ ~ ~ ~ ~ S . ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ' ~ ~ ~ ' The separate existence of two individual tautomeric forms of the S-methyl derivative of 5,5-diphenyl-2-thiohydantoin(84 and 85), which had been originally claimed on the basis of IR evidence, has been proved by X-ray structure determination." Although the hydantoin ring is essentially planar, in some cases the deviation from planarity is not negligible.'I4 A great variety of N-H N and especially N-H * * * 0 hydrogen bond systems have been The first type is particularly strong in some hydantoins containing basic centers. The solid structure of 2-thiohydantoin does not show NH * - S=C hydrogen bonds.' l6 However, some 24hiohydantoin derivatives have shown N' -H * S=C hydrogen bonds.21 +

A. Camerman and N. Camerman, Acta Crystallogr., Sect. B B27(11),2205 (1971). P. H. Bird, L. D. Co1ebrook.A. R. Fraser,and H.G.Giles.J.C.S., Chem. Commun. 6,225( 1974). '05 R. W. Miller and A. T. McPhail, J . Chem. Res., Synop. 10,330(1979). ' 0 6 M. H. Koch, G. Germain, J. P. Declerq, and Y.Dusansoy, Acta Crystallogr., Sect. B B31(10), 2547 (1975). '07 P. Smith-Verdier,F. Florencio, and S . Garcia-Blanco, Acta Crystallogr., Sect. B B33(11),3381 (1977). '08 P. Smith-Verdier, F. Florencio, and S . Garcia-Blanco,Acta Crystallogr, Sect. B B35(1), 216 ( 1979). '09 F. Florencio, P. Smith-Verdier, and S . Garcia-Blanco, Acta Crystallogr., Sect. B B38, 2089 (1982). 'lo J. Vilches, F. Florencio, P. Smith-Verdier, and S . Garcia-Blanco, Acta Crystallogr., Sect. B B37(1),201 (1981). 'I1 J. Vilches, F. Florencio, P. Smith-Verdier, and S . Garcia-Blanco, Acta Crystallogr., Sect. B B37(11),2076(1981). 'I' J. Vilches, F. Florencio, and S . Garcia-Blanco, Acta Crystallogr., Sect. B B37(2), 361 (1981). ' I 3 K. Lempert, J. Nyitrai, K. Zaner, A. Kalman, Gy. Argay, A. J. M. Duisemberg, and P. Sohar, Tetrahedron 29(22),3565 (1973). 'I4 E. Arte, B. Tinant, J. P. Declerq, G. Germain, and M. Van Meerssche, Bull. Soc. Chim. Belg. 89(5), 379 (1980). 'I' R. E. Cassady and S . W.Hawkinson, Acta Crystallogr., Sect. B B38, 164 (1982). ' I 6 L. A. Walker, K. Folting, and L. L. Merritt, Acta Crystallogr., Sect. B B25,88 (1969). '17 H. Fujiwara and J. M. Van der Veen, J.C.S. Perkin I! 5,659 (1979). '03

'04

' '

Sec. IV.A]

HYDANTOINS

209

G. QUANTUM MECHANICAL CALCULATIONS Extensive MO calculations for bond lengths and angles of 1-phenyl-2-thio5-carbomethoxymethylhydantoin have been reported.218 He(1) excited photoelectron spectra of hydantoin and 1-methyl-hydantoin are assigned by comparison with the spectrum of succinimide and by INDO/S cal~ulations.~

IV. Reactivity of Hydantoins and Their Derivatives As would be expected, hydantoins and thiohydantoins can react with nucleophilic and electrophilic as well as with other types of reagents.

A. ELECTROPHILIC SUBSTITUTION 1. Protonation On protonation in strongly acidic solution, hydantoin cations (86 or 87) are formed.220UV spectral changes indicate that 2,4-dithiohydantoins are first protonated on the sulfur atom at the 2-position, while 4-hydantoins are protonated on oxygen at the 2 - p o ~ i t i o n . ' Both ~ ~ *0~ ~and ~ S-protonation are separately observed in 2-t hiohydantoins.

''

2. Reactions with Lewis Acids Oxidation and the benzilic acid rearrangement occur during the reaction leading from benzoin to 5,5-diphenyldithiohydantoin(88) (Scheme 9). The 21*

R. Baltrusis, Z. Beresnevicius, I. Vizgaitis, and Yu. V. Gatilov, Khim. Geterotsikl. Soedin. 12, 1669 (1981).

D. Ajo, M.Casarin, G. Granozzi, A. Poli, and E. Tondello, J. Mol. Struct. 82,277 (1982). 220 W. I. Congdon and J. T.Edward, Can. J. Chem. 50,3767 (1972). J. T. Edward and J. K. Liu, Can. J . Chem. 47(7), 1123 (1969). 2 2 2 J. T. Edward and S. Ch. Wong, Can. J. Chem. 57(15), 1980 (1979). 219

210

[SeC. 1V.A

C. AVENDARO L6PEZ AND G.GONZALEZ TRIG0

product on treatment with AICI, undergoes a reductive retrobenzilic acid rearrangement (Section 11,E).However, in the benzilic acid rearrangement the phenyl group migrates anionically; the migration of the phenyl group in this case is most likely accomplished c a t i o n i ~ a l l y . ~ ~ ~ - ~ ~ ~

- 1,”;s Ph

Ph-CH-C-Ph

I

J.PISS 2. I . oxidetion WNH,),

II

p h Ph

k

x S

AICI,

Ph

H

OH 0

H

SCHEME 9

5,5-Diaryl-2,4-dithiohydantoins, when refluxed with BF, dimethyl etherate or mixtures of the former reagent with BF, in toluene or chlorobenzene, are selectively methylated at the S2 atom and/or undergo the above-mentioned rearrangement to yield imidazole derivatives (89).226

Ph P h k F s H

-

Ph ’ k YN S M e H

-

Ph Ph2 PN S M e

3. N-A lkyla t ion Hydantoins can easily be alkylated in the N-3 position by treatment with alkyl halides in alkaline solution in protic or aprotic solvents. Other alkylating agents include dimethyl sulfate and diazomethane. Amide nitrogen (N- 1) alkylations are well-known in 3-substituted hydantoins, but they occur under more severe conditions than the simple N-3 imide alkylations. For instance, N-3 substituted hydantoins are N-1 alkylated with good yields in D M F and sodium h ~ d r i d e . ~Mono-N~’ 1-alkylated hydantoins can be obtained by protecting the imide nitrogen with an aminomethyl group, followed by alkylation of the amide nitrogen and the removal of the protecting group by J. Nyitrai, Acta Chim. Acad. Sci. Hung. 51,95 (1967). E. Koltai, J. Nyitrai, K. Lempert, and L. Bursics, Chem. Ber. 104,290 (1971). R. Markovits-Komis, J. Nyitrai, and K. Lempert, Chem. Ber. 104, 3080 (1971). 2z6 J. Fetter, J. Nyitrai, and K. Lempert, Tetrahedron 27(23), 5933 (1971). 0.0.Orazi, R. A. Corral, and H. Schttenberg, J.C.S. Perkin Trans. I I , 219 (1974). 223 224

”’

”’

Sec. ,IV.A]

21 1

HYDANTOINS

mild alkaline hydrolysis.’” However, in intramolecular processes, such as the conversion of 90 to 91, only amide cyclized monomers have been ~btained.~” If strongly alkaline conditions or phase-transfer catalysis is used, N- 1,N-3disubstituted hydantoins are ~ b t a i n e d . ’ ~ ~ * ~ ~

’

n = 2,3

n = 2,3

The products of alkylation of thiohydantoins are kinetically controlled and hence are frequently the less stable S-alkyl compounds.’ 3**z3z Methylation products of 2-thio- and 2,4-dithiohydantoins exist almost entirely in one tautomeric form (92)or the other (93)depending on the solvent.’53 5Monosubstituted 2,4-dithiohydantoins exist as the tautomer (94), and alkylation takes place on sulfur.”’

Rck X

-

R’

H

SCH,

HS Ph

$“;-, H

S-Methyl derivatives of 5,5-diphenylmono and dithiohydantoins may be demethylated by the hydrogen sulfide anion, thiolate anions, or phosphorus pentasulfide. The latter simultaneously converts carbonyl to thiocarbonyl groups. The S-benzyl groups may also be removed by briefly boiling with benzene in the presence of aluminum chloride. The removal of N-3-benzyl groups needs more vigorous condition^.'^^ 0.0.Orazi and R. A. Corral, Expmientia 21,508 (1965). E. E. Smissman, P. L. Chien, and R. A. Robinson, J . Org. Chem. 35(11), 3818 (1970). 230 G. G. Trigo, C. Avendailo, I. Varela, and M. Martinez, An. Quim. 74(7-8), 1090 (1978). C. Pedregal, G . G . Trigo, M. Espada, and J. Elguero, J . Heterocycl. Chem. 21,477 (1984). 232 N. Kornblum, R. A. Srniley, R. K. Blackwood, and D. C. Iffland, J . Am. Chem. SOC.77,6261 2z8

229

233

(1955). G. Domany. J. Nyitrai, K. Zaner, K. Lempert, and S. Bekassy, Acta Chim. Acad. Sci. Hung. 80(1), 101 (1974).

212

C. AVENDARO L6PEZ AND G. GONZALEZ TRIG0

[Sec. 1V.A

,

Direct N-1 and S-alkylation of 5,5-disubstituted 2-thiohydantoins has been rep~rted.~' Some N-3-substituted hydantoins, such as 95, lead to N-bridgehead bicycles (W), which are oxygen analogues of levamisole and are powerful alkylating agents.234 The intramolecular process is controlled by the thermodynamic stabilities of the two possible bicyclic products resulting from N- or 0alkylati~n.~'

In contrast, reaction of 5,5-diphenylthiohydantoin with l-bromo-2chloroethane generates two isomeric imidazo(2,l-b)thiazole derivatives (97 and 98) through intramolecular S,N-dialkylati~n.~~' The formation of imidazo(2,l-b)thiazoles by this kind of process is rather common.236 Similarly, reaction with 1,3-dibromopropane gives two isomeric diphenyIimidazothiazines.2 3 8 's2

CH,CO,Et

(97)

(98)

(99)

5-Substituted 2-thiohydantoins and ethyl 4-bromacetoacetate give $6dihydroimidazo(2,2-b)thiazolederivatives (99).239 N-Alkoxymethyl derivatives are formed from the hydantoin alkali salt with chloromethyl alkyl ether"O but the alkoxymethylation of alcohols, using K. Okada, J. A. Kelley, and J. S . Driscoll, J . Heterocycl. Chem. 14(3), 51 1 (1977). K. Okada, J. A. Kelley, and J. S. Driscoll, J . Org. Chem. 42(15), 2594(1977). 236 E. G. Delegan, 1. V. Smolanka, and Yu.V. Melika, Khim. Geterotsikl. Soedin. 11, 1572 (1974). 237 J. Karolak-Wojciechowska, M. W. Wieczorek. K. Kiec-Kononowicz, A. Zejc, M. Mikolajezyk, and A. Zatorskii, Tetrahedron 36(8), 1079 (1980). 238 J. Karolak-Wojciechowska, M. W. Wieczorek. K. Kiec-Kononowicz, A. Zejc, M. Mikolajezyk, and A. Zatorskii, Tetrahedron 37(2), 409 (1981). 239 R. B. Blackshire and C. J. Sharp, J. Chem. Soc. C 21,3602 (1971). 240 J. A. Vida, M. H. ODea, and C. M. Sarnour, . I Med. . Chem. 18,383 (1975). 234

23s

Sec. IV.A]

213

HYDANTOINS

dialkoxymethane and phosphorus pentoxide, has also been applied.241NAlkylation with chloroformate esters has been The Mannich reaction gives N-3-aminomethyl derivative^.^,^-^,^ These products have been proposed as prodrugs for a series of drugs containing a primary aromatic amino group to prevent metabolic inactivation by Nacetylation (Scheme

-

CH2-NHR3

‘%To+

R2

H

C H 2 0 + R’NH,

R k f o R2

H

SCHEME 10

Reduction with NaBH, in Me,SO of the N-3-aminomethyl derivatives has been also proposed as a method for N-methylation of aromatic primary amine~.~,*Alternatively, N - 1- or N-3-aminomethyl derivatives can be obtained by reaction of N-1- or N-3-halohydantoins with diazomethane and the ami~~e.~,’ Aminoethylations with eth~lenimine~~’ and Michael reactions have also demonstrated a preference for the acidic imide function. Thus the N3-H group adds to acetylene to give N-3-vinylhydantoin~~~~ and to activated ethylenes, such as acrylonitrile or 4-vinylpyridine, to give N-3-substituted h y d a n t ~ i n s . ~ ’ ~Under ~ ’ ~ ~ some ~ ’ ~ conditions 1,3-disubstituted hydantoins are ~btained.~” 2-Thiohydantoins behave as S-nucleophiles and, with acrylic acid, give compounds 100, which cyclize by acetic anhydride to 6,7-dihydro-3,3disubstituted SH-imidazo(2,l-b)(1,3)thiazine-2(3H)-S-diones(101).254 J. Gal, J . Pharm. Sci. 68(12),1562 (1979). J. A. Vida, Tetrahedron Lett. 37,3921(1972). 243 0.0. Orazi and R. A. Corral, Tetrahedron 15,93(1961). 244 M.B. Winstead, D. E. Barr, C. R. Harnel, D. J. Reun, H. I. Parker, and R. M. Newmann, J . Med. Chem. 8(1). 1 17 (1965). 0.0.Orazi and R. A. Corral, An. Asoc. Quim. Argent. 51(2), 180(1963). 246 B. Sucka-Sobstel and A. Zejc, Diss. Pharm. Pharmacol. 22(1), 13 (1970). 24’ H. Bundgaard and M. Johansen, Int. J . Pharm. 8(3),183 (1981). K. Horiki, Heterocycles 5(1),203 (1976). 249 R. A. Corral and 0.0.Orazi, Tetrahedron Lett. 25, 1693 (1964). ”O J. W. Shaffer, R. Scheasley, and M. B. Winstead, J . Med. Chem. 10,739(1967). Wn. 0. Jones, British Patent 846,601 (1960)[ C A 55,10471 (1961)l. 252 Ch. Chia and Ch. Hsing, Hua Hsueh Hsueh Pao 29(6),433 (1963). J. W. Shaffer, E. Steinberg, V. Krimsley, and M. B. Winstead, J. Med. Chem. 11(3),462 (1968). 2’4 J. Fetter, K. Harsanyi, J. Nyitrai, and K. Lempert, Acta Chim. Acad. Sci. Hung. 78(3), 325 (1973). 241

”’

”’

’’’

214

C. AVENDARO L6PEZ AND G . GONZALEZ TRIG0

R>x

R2

N

[SeC. 1V.A

&To

S

Jd

0

0

4. N-Acylation When hydantoins are treated with acetic anhydride, sodium hypochlorite, or nitiric acid, substitution takes place at the N-1 position, followed by the formation of a 1,3-disubstituted hydantoin. Intramolecular processes yield only the amide cyclized products (102).255*256 Thiohydantoins could form S-acyl compounds, which would speedily rearrange to the more stable N-acyl compound^.^ 2,CDithiohydantoin is converted by acetic anhydride to 1,3-dia~etyl-2,4-dithiohydantoin.~~’ Brief fusion of a mixture of isopropenyl esters and an acid catalyst with hydantoins gives high yields of N-acylated Treatment of hydantoins with trihalomethylsulfenyl chlorides yields N-3-substituted and N-l,N-3 disubstituted compounds, which exhibit antifungal activity.2593Aryl- or 3-alkylsulfonylhydantoins are prepared by direct acylation with RS02CI in C5H5Nor Et3N.260 Acid or basic hydrolysis of 1,3-diacyl and 1,3-disulfonyl derivatives gives 3-Acetyl-1,5,5-trimethylhydantoinexhibits a remarkable N-1 regioselectivity in acylation reactions of amines or phenols bearing alcoholic groups (Scheme 1l).262Nitrosation in an aqueous medium gives satisfactory yields in only a few examples.263The reaction with sodium nitrite and methanesulfonic acid in dichloromethane affords l-nitro~ohydantoins.~~~ 1,3-

”’ J. L. Szabo, F. R. Scholer, and K. H. Wildrick, J . Med. Chem. 9, 142 (1966). H. R. Henze and R. J. Speer, J . Am. Chem. SOC.64,522 (1942). ”’A. H. Cook, I. Heilbron, and A. L. Levy, J . Chem. SOC.,201 (1948). 256

”*

E. S. Rothman, S. Serota, and D. Swern, J . Org. Chem. 29(3),646 (1964). R. J. W. Cremlyn, J . Chem. SOC.2,6240 (1964). T. Nakamura and K. Nakamura, Japanese Patent 70/24,777 (1970) [CA 74,76419 (1971)l. 2 6 1 S. Umemoto, T. Nakamura, and K. Nakamura, Japanese Patent 70/24, 778 (1970) [CA 74, 76416 (1971)l. 2 6 z 0.0.Orazi and R. A. Corral, J . Am. Chem. SOC.91(8), 2162 (1969). 263 E. H. White, J . Am. Chem. SOC.77,6008 (1955). 264 0.0.Orazi, R. A. Corral, and A. 0.Sanchez, Synthesis 4,205 (1972). 259

Sec. IV.A]

215

HY DANTOINS

+G

Bisdithiocarboxylic acid derivatives of hydantoins are obtained by treatment with alkali and CS2.265 M Me

e

h yAc o

O H e C H 2 0 H

(j

N

I

Me

CH,OH 91%

CH,OAc 9%

SCHEME I1

5. Halogenation Although halogenation of the hydantoin ring with several agents occurs preferentially at position 3, monohalogenation of nitrogen-unsubstituted hydantoins leads in all cases to the 1-halo derivative as a result of the intermediate formation of the 1,3-dihalo compound and later transfer of the halogen atom at the N-3 position to another hydantoin molecule. N-Chloro derivatives have been prepared, using various chlorinating agents' and N-bromo derivatives by employing bromine in alkaline solution. N-Monoiodo compounds are obtained by treatment of the silver derivative of the hydantoin with iodine while N-l,N-3-diiodo derivatives are prepared by reaction of hydantoins with iodine monochloride.266 Several halohydantoins have been patented as bleaching agents, antiseptics, and fungicides (Section V),and as N-halosuccinimides; these halo derivatives are potent halogenating and oxidizing reagent^.^^^-^^' 1,3-Diiodo-5,5-dimethylhydantoinshows general applicability for nuclear iodination of aromatic and heteroaromatic compounds activated by electrondonating substituents, and, like N-iodosuccinimide, reacts with enol acetates, affording a-iodo ketones in good yields.2703-Bromo-5,5-dimethylhydantoin is particularly useful in regio- and stereo-controlled conversion of unsaturated acids, such as 103, to bromo lactones, such as lM.270aAllylic X'

T. Takeshima, M. Ikeda, M. Yokoyama, N. Fukada, and M. Muraoka, J.C.S. Perkin 13,692 (1979).

R. A. Corral and 0.0. Orazi, J . Org. Chem. 28,1100 (1963). Y. Ishii, T. Ito, and Sh. Kato, Kogyo Kagaku Zasshi 61, 1254 (1958). 268 M. J. Fumarola and 0. A. Orio, An. Asoc. Quim. Argent. 60(1), 61 (1972). 269 0.D. Madoery and 0.A. Orio, An. Asoc. Quim. Argent. 58(4), 277 (1970). 270 0.0. Orazi, R. A. Corral, and H. E. Bertorello, J . Org. Chem. 30,1101 (1965). 270a Ch. Cook and Y. Chung, Arch. Pharm. Res. 4(2), 133 (1981). 266

267

216

C. AVENDARO L6PEZ AND G . GONZALEZ TRIG0

[SeC. 1V.A

halogenation with l-bromo-3,5,5-trimethylhydantoin has been studied,271 and significant reactivity differences with phenylpropenes under Ziegler conditions have been 1,3-Dibromo-5,5-dimethylhydantoin has been used for stereospecific bromohydroperoxylation of 4,4-dimethyl-3,5-diphenyl-4H-pyra~ole.~ 73

(103)

(1W

1-Chlorohydantoins react with methyl alkyl sulfides to give N-sulfonium salts (105), which undergo with tertiary amines a Stevens rearrangement with formation of unstable imidates (106), which isomerize to 107 by heating.274 Similarly, 1,3-dichloro-5,5-dimethylhydantoin and methyl sulfides gives disulfonium salts, which undergo Stevens rearrangement in the presence of tertiary amines. 7 5

R k X 0 -R 2 J S+ I

R

R’

R

H

-R 2 1 0

,CHzSR

A

OCHZSR

R

N

H

‘CH, (105)

(W

(107)

5-Unsubstituted 2-thiohydantoins are brominated with bromine in acetic acid to give 5-bromo derivatives, which are intermediates in several reactions. Thus by refluzing with either thiourea or thioacetamides, thiazolothiohydantoin derivatives (108) are The electrophilic reactivity of 5-halohydantoins with several aromatic systems has been studied.277 5-Halohydantoins undergo the Arbuzov reaction, giving bidentate ligands (109).278 271

A. R. Suarez and 0.A. Orio, An. Asoc. Quim. Argent. 65.163 (1977).

’”V. T. Balzaretti, A. R. Suarez, and 0.A. Orio, An. Asoc. Quim. Argenr. 68, 163 (1980). M. E.Landis, R. L. Lindsay, W. H.Watson, and V. Zabel, J . Org. Chem. 45(3), 525 (1980). E. Vilsmaier, R. Bayer, 1. Laengenfelder, and U. Welz, Chem. Ber. 111(3), 1136 (1978). 2 7 s E. Vilsmaier, R. Bayer, U. Welz, and K. Dittrich, Chem. Ber. 111(3), 1147 (1978). 276 B. Dash and S. K. Mahapatra, Curr. Sci. 39(24),559 (1970). 2’7 H.E.Zangg, J. E. Leonard, and D. L. Arendsen, J . Heterocycl. Chem. 11(5),833 (1974). M. Willson, T. Bouisson, and F. Mathis, C. R. Hebd. Seances Acad. Sci. 295,567 (1982). 273 274

Sec. IV.A]

HYDANTOINS

217

6 . Hydantoins as Heterocyclic Compounds Containing Active Methylene Groups Besides the previously mentioned halogenation in the C-5 position, hydantoins having a free methylene group condense with aldehydes (especially aromatic aldehydes) or their precursor^.^'^ 2-Thiohydantoins condense more readily than do the corresponding hydantoins.' These C-5-unsaturated hydantoin derivatives may be reduced by any common reducing agents as well as by catalytic methods' and are versatile synthetic intermediates for the preparation of amino acids280and for other reactions.281 Treatment of the 5-arylidene derivatives of 1,3-diphenyl-2-thiohydantoin with malononitrile affords tetrahydropyrano(2,3-d)imidazoles (1lo), while 3phenyl- or unsubstituted 2-thiohydantoins originate pyrrolo(1,2-c)imidazoles (111). These products are also obtained in a Michael-type reaction of 2thiohydantoins with activated nitriles.282

Some 5-benzal-2-thiohydantoins,especially the 5-anisal derivative, have been selected and proposed for spectrophotometric determination of pall a d i ~ m , ~and ' ~ several condensation products of aldehydes and hydantoin T. Moriya, K. Hagio, and N. Yoneda, Chem. Pharm. Bull. 28(6),1891 (1980). U. Jacoby and F. Zymalkowski, Arch. Pharm. (Weinheim, Ger.) 304(4), 271 (1971). 281 B. A. Ibin, G. V. Rutkovskii, E. G. Sochilin, and I. Y. Tsereli, Zh. Org. Khim. 8(3),640 (1972). H. A. F. Daboun, S. E. Abdou., M. M. Hussein, and M. H. Elnagdi, Synthesis, 502(1982). M. T. Montana Gonzalez and J. L. G6mez Ariza, Microchem. J . 25(3),360 (1980).

'19

218

C. AVENDARO L 6 P E Z AND G. GONZALEZ TRIG0

[Sec. 1V.A

or 2-thiohydantoin have been prepared as possible antituberculosis substances.284 Condensation products of aromatic aldehydes and 4-thiohydantoins react with Grignard reagents to give the colorless products 112. Compounds 113 and 114 are formed by alkylation and diazomethane addition These condensation products also react as dienes with acrylonitrile, ethyl acrylate, and other dienophiles giving adducts 115.286

X

= CN, C0,Et

Treatment of 2-thiohydantoins, l-phenyl-2-thiohydantoins,and 1,2diphenyl-2-thiohydantoins with aryldiazonium salts yields 5-arylazo-2thiohydantoins (116) and with p-Me,NC6H4N0 the anil 117, in which the exocyclic azomethine linkage can be cleaved by PhNHNH, and/or AcOHHCI to give 118.287

The tautomerism of some 5-arylazo-2-thiohydantoin derivatives as a criterion of their acidity has been studied, and the apparent pK, values have been discussed in terms of Hammett correlations.288 284

286

H. Tielemann, Sci. Pharm. 39(1),8 (1971). A. F. A. Shalaby, H. A. Daboun, and S.S.M. Bghdadi, Z. Naturforsrh., B: Anorg. Chem., Org. Chem. B29( 1 -2), 99 [ 19741. H. A. Daboun, M. A. Abdel Aziz, and F. A. Abdel Aal, Heterocycles 19,677 (1982). A. F. A. Shalaby, H. A. Daboun, and M. A. Abdel Aziz, Indian J. Chem. 12(6), 577 (1974). H. M. Fahmy, M. A. A. Aziz, M. Abortabl, and M. A. Azzeu, Indian J . Chem. 20A(6), 593 (1981).

Sec. IV.B]

219

HYDANTOINS

1-Phenyl-4-thiohydantoinalso couples with aryldiazonium salts to give colored 5-arylazo derivatives. The introduction of the electron-withdrawing arylazo group activates the hydantoin ring as well as the thione

B. REACTIONS WITH NUCLEOPHILES 1. Hydrolysis Hydantoins and thiohydantoins are hydrolyzed by alkaline media to give the corresponding ureido or thioureido acids, respectively (Section ILA), which under very vigorous conditions give amino acids.’ Several detailed kinetic investigations on the mechanism of hydrolysis of hydantoin derivatives have been published since the first report of Ingold and cow o r k e r ~Two . ~ ~parallel ~ reactions are proposed: attack of OH- on either the Blagoeva et aL6 have free hydantoin ring or on its N-3 established the general validity of the mechanism shown in Eq. (1).

rJo rxo

0

0

=

H

N H

0-

=H O t J 0 H

= Of H

KO

(1)

The alkaline hydrolysis of hydantoins appears to be faster than that of the corresponding 2-thiohydantoins, even when account is taken of the greater degree of ionization of the latter compounds and its probable effect on rates.3 Studies on alkaline hydrolysis of 2-thio-5-arylidenehydantoinsand some of their derivatives have been r e p ~ r t e d . ~ ~Ho ~ wever, ” ~ ’ very little attention has 289

290

29’

A. F. A. Shalaby, H.A. Daboun, and S. S. M. Boghdadi, Z . Naturforsch., B : Anorg. Chem., Org. Chem. 318(6), 865 (1976). C. K. Ingold, S. Sako, and J. F. Thorpe, J . Chem. Soc., 1177 (1922). B. A. Ivin, G. V. Rutkowskii, E. G. Sochilin, and I. Yu.Tsereteli, Zhr. Org. Khim. 8,840, 1951 (1972).

292

B. A. Ivin, G. V. Rutkovskii, T. N. Rusavskaya, and E. G. Sochilin, Zhr. Org. Khim. 11,2188 ( 1975).

294

B. A. Ivin, G. V. Rutkovskii, and E. G. Sochilin, Zhr. Org. Khim. 9, 179 (1973). B. A. Ivin, G. V. Rutkovskii, S. A. Andreev, and E. G. Sochilin, Zhr. Org. Khim. 9,420, 2194

295

(1973). G. D. Vogels, F. E. de Windt, and W. Bassi, Recl. Trao. Chim. Pays. Bas 88,940 (1969).

293

296

2y7

B. A. Ivin, T. N. Rusavskaya, A. I. Dyachkov, G. U. Rutkovskii, and Yu.A. Ignat’ev, Khim. Geterotsikb Soedin. 3,406 (1979). B. A. Ivin, T. N. Rusavskaya, A. 1. Dyachkov, and G. V. Rutkovskii, Khim. Geterotsikl. Soedin. 6,813 (1979).

220

C. AVENDARO L6PEZ AND G . GONZALEZ TRIG0

[SeC.

1V.B

been paid to the alkaline hydrolysis of derivatives with electron-withdrawing derivatives. These groups attached to C-5, as in the 5-arylazo-2-thiohydantoin compounds are cleaved by aqueous sodium hydroxide and rearrange to different products, depending on the N-1 sub~tituents.~~' In 1-acyl-2-thiohydantoins, the acyl group is easily attacked by hydroxide ion, even in very dilute alkali, making possible the stepwise degradation of peptides in Schlack and Kumpf's procedure." 2,4-Dithiohydantoins appear to be resistant to alkaline hydrolysis, perhaps because they are so completely converted to the conjugate base that hydrolysis rates become neglibible.' Certain N-3-aminoalkylhydantoinsundergo hydrolytic ring opening under very mild conditions, suggesting the intramolecular mechanism shown in Scheme

R

R

R

SCHEME 12

Since the discovery of hydantoin in 1861, when Baeyer isolated it in his uric acid studies, that system has been an important precursor of a-amino acids owing to its lability toward alkali, especially for those acids that are difficult to prepare by other methods.300Furthermore, the stereochemical courses of the Bucherer-Bergs and Read methods of synthesis for hydantoins (Section WE), permit the preparation of epimeric amino acid^.^^'-'^^ Some of these amino acids have been tested as possible tumor growth inhibitor^,^^^."^ as metabolism-resistant amino acid analogues for transport system s t ~ d i e s , ~ ~ . ~ ~ '

*"

A. F. A. Shalaby, H. A. Daboun, and M. A. Abdel Aziz, Z . Natursforsch., B: Anorg. Chem., Org. Chem. 338,937 (1978). 299 C. F. Spencer, J . Heterocycl. Chem. 10(4), 455 (1973). 300 E. B. Henson, P. M. Gallop, and P. V. Hanschka, Tetrahedron 37(15), 2561 (1981). 301 R. J. W. Cremlyn, J . Chem. Soc., 3977 (1962). 302 G. Nathansohn, G . F. Odasso, C. R. Pasqualucci, and E. Testa, Steroids 5(3), 263 (1965). 303 Y. Maki, M. Sato, and K. Obata, Chem. Pharm. Bull. 13(2), 1377 (1965). 304 R. J. W. Cremlyn, R. M. Ellam, and T. K. Mitra, Indian J . Chem. 8(3), 218 (1970). 30' F. F. Knapp, J . Org. Chem. 44(6), 1007 (1979). 306 T. A. Connors and W. C. J. Ross, J . Chem. SOC.,21 19 (1960). 307 L. Nicole and L. Berlinguet, Can. J . Chem. 40,353 (1962). 308 G . G. Trigo, C. Avendaiio, E. Santos, H. N. Christensen, and M. Handlogten, Can. J . Chem. 58(21), 2295 (1980).

Sec. IV.B]

22 1

HYDANT~INS

and as intermediates in the synthesis of spiro-4'-oxazolidines (119),jo9 pyrrolines (120),310and analgesic-type compounds (121).j1

(119)

urn)

(121)

D-Amino acids, used as intermediates for semisynthetic penicillins and cephalosporins, have been obtained by stereospecific enzyme-catalyzed hydrolysis of ~~-hydantoins.'' The enzymes have been described as hydantoinase and N-carbamoyl-D-amino acid amid~hydrolase,~although some authors identify the former with dihydr~pyrimidinase.'~~ Amino acids have also been obtained by acid hydrolysis of hydantoins and 2-thiohydantoins under relatively drastic conditions. 4-Thiohydantoin is hydrolyzed with hot concentrated hydrochloric acid to hydantoin, and boiling 20% aqueous chloroacetic acid completely removes sulfur from 2,4-dithiohydantoin to form hydantoin derivatives. (Scheme 8). These reactions reflect the intrinsic stability of the hydantoin ring.

'

'*'

2. Ammonolysis 4-Thio- and 2,4-dithiohydantoins react with ammonia or amines at the 4position to give 4-imino compounds (Scheme 8). Some 2,4-dithiohydantoins react with ethanolamine at the 2-position to give imino compounds, probably because the 4-position is too hindered.' An unusual base-catalyzed cleavage reaction of the fused spirothiazolidine ring of the hydantoin 122 to 123 occurs by reaction with liquid ammonia.315 2-Thiohydantoins, like hydant~ins,'.''~react with hydrazine, and probably with amines, to give hydrazides and amides of the thioureido acids.'" '09

'I0

'I1 'I2

'I4

'I5

'I6 'I7

P. Michon and A. Rassat, J. Org. Chem. 39(14),2121 (1974). K. E.Schulte, J. Reisch, and M. Plener, Arch. Pharm. (Weinheim, Ger.)303(5),435 (1970). P.W. Feit and H. H. Freit, British Patent 1,115,817(1968)[ C A 70,28834(1969)J D. Dinelli, W. Marconi, F. Cecer, G .Galli, and F. Morisi, Enzyme Eng. 3,477(1978). R. Olivieri, E. Fascetti, L. Angelini, and L. Degan, Biotechnol. Bioeng. 23(10),2173 (1981). H.Yamada, S. Takakasshi, Y. Kii, and H.Kumagau, J. Ferment. Technol. !%(5), 484, 492 (1978). A. Takamizawa and S. Matsumoto, Chem. Pharm. Bull. 21(6),1300(1973). S. R. F. Kagaruki, M. R. Khan, and H.Wevers, Pak. J. Sci. lnd. Res. 24,99 (1981). J. T.Edward and S.Nielsen, J . Chem. Soc., 5084 (1957).

222

C. AVENDAAO L 6 P E Z AND G. GONZALEZ T R I G 0

[SeC.

1v.c

R' I

R' = Ar Rz = Me

Formation of 3-aminohydantoin derivatives in some cases implies ring opening-ring closure of the hydantoin ring.'".' l 9 In some of these processes, such as the reaction of the methylmercaptohydantoin 124 to form the glycocyamidine (125), rearrangements are involved.320

ArCH

ziAr XNH2 SMe

HzNNHz,

ArCH

N

NAr

H

c. REACTIONS W I T H REDUCING AGENTS Lithium aluminum hydride (LiAlH,) reductions of hydantoins have been reported to yield a variety of products depending on the C-5, N-1, and N-3 substituents. Imidazolones (126)321 and 4-hydroxy-24midazolidinones (127)97-'22 are formed from room temperature reductions, while slightly more vigorous conditions (reflux, ether or THF) give 127,97 2-imidazolidinones 2 4 Re(128),' 'J24 imidazoles (129),32 and imidazolidines (130).32 ' 9 '

R. A. Wildonger and M. B. Winstead, J. Med. Chem. 10(5), 981 (1967). K. Lempert, Chem. Ber. 96,2246 (1963). 320 H. A. Daboun and Y.A. Ibrahim, J . Heterocycl. Chem. 19,41(1982). 3 2 1 1. J. Wilk and W. Close, J . Org. Chem. 15, 1020 (1950). 3 2 2 S.Cortes and H. Kohn, J . Org. Chem. 48(13), 2247 (1983). 323 F. J. Marshall, J . Am. Chem. SOC.78,3696(1956). 324 E. d e la Cuesta, P. Ballesteros, and G. G. Trigo, Heterocycles 16(10), 1647 (1981). 31*

319

Sec. IV.C]

223

HYDANTOINS

cently, selective ring opening of 3-substituted hydantoins to produce N methylethylenediamines (131) has been reported.322

I

R'

I

R'

I

(1299)

I

R'

I

R'

R'

(130)

(131)

Little is known about the behavior of hydantoins in dissolving metal reductions. The reaction of hydantoin (132) with 5 equivalents of lithium in tert-butyl alcohol and liquid ammonia gives the 4-imidazolin-2-one 133. The use of methanol instead of tert-butyl alcohol gives a mixture of reduced products, probably originated by ring cleavage as well as by reduction.325

H

H

(132)

(133)

I

R' (134)

Because of its greater polarization, the thiocarbonyl group would be expected to be more easily reduced than would the carbonyl group. 2Thiohydantoins are reduced by sodium in ethanol to give 4-imidazolidinones under conditions that do not affect hydantoins. Reduction with Raney nickel yields the same products, although the less reduced 4-imidazolones are obtained under some conditions. If the 5-substituents are alkyl instead of phenyl, a-N-formylamino amides (134) become the major products of Raney nickel reduction. 4-Thiohydantoins are reduced by this reagent to 2imidazolidinones and 2,4-dithiohydantoins to irnida~oles.~ 325

H. R. Divanfard, Y. A. Ibrahim, and M. M. JouilliC, J . Heterocycl. Chem. 15,691 (1978).

224

C. AVENDARO L6PEZ AND G. GONZALEZ T R I G 0

[SeC.

V.A

D. OTHER SIGNIFICANT REACTIONS As predicted in 1965, some hydantoin derivatives are precursors of carbonium-immonium ions, which are powerful e l e ~ t r o p h i l e s .These ~~~ include the 4-hydroxy-2-imidazolidinones(Section IV,C). 5-Alkoxyhydantoins (135) undergo successful inter- and intramolecular amidoalkylations through cation intermediates

(135)

(1%)

(137)

3-Phenyl-5-methoxyhydantoinsare also precursors of dieneophiles, such as 137, reacting thermally or under acid catalysis with dienes to give Diels-Alder

adducts. The acid-catalyzed reactions are more stereospecific than the thermal reactions.328 In the total synthesis of the antibiotic ~treptonigrin,~~' the pyridine ring has been constructed in this fashion. 5-Alkyl-5-aminohydantoins are also suitable intermediates to obtain 5-alkyl-5-substituted derivatives.' 29 Finally, optically active 3-hydroxyhydantoins have been designed as acyl activating reagents for asymmetrically selective peptide s y n t h e s i ~ . ~ ~ ~ * ~ ~ '

V. Uses and Applications A. HYDANTOINS AS MEDICINAL PRODUCTS Although the hydantoin ring itself does not present any medicinal activity, the 5,5-disubstituted hydantoins have found wide use in medicine. They have mainly been considered as anticonvulsant agents, having been reviewed in H. E.Zangg and W. B. Martin, Org. React. (N.L) 14,60 (1965). D. Ben-Ishai, G. Ben-Et, and A. Warshawsky, J . Heterocycl. Chem. 7, 1289 (1970). 328 D. Ben-Ishai and E. Goldstein, Tetrahedron 27,3119 (1971). 329 S. M. Weinreb, F. Z. Basha, S. Hibino, N. A. Khatu, D. Kim, W. E. Pye, and T. Wu, J. Am. Chem. SOC.104(2), 536 (1982). 330 T. Teramoto, T. Kurosaki, and M. Okawara, Tetrahedron Lett. 18, 1523 (1977). 3 3 * T. Teramoto, T. Kurosaki, and M. Okawara, Pept. Chem. 15,43 (1978). 326

32'

Sec. V.A]

HYDANTOINS

225

1950' and 1963.332The hydantoin derivative which has achieved the greatest prominence in this field is 5,5-diphenylhydantoin (Phenitoin, Dilantin), recommended since 1938 for the treatment of epilepsy by Merritt and P ~ t m a n . 'Because ~~ of its regulating effect on the bioelectric activity of the nervous system, it is used widely as an anticonvulsant and cardiac antiarDespite important toxic side effects, it is still the anticonvulsant of choice for epilepsy treatment.335 Several analytical, spectrophotometric, and, more recently, GLC techniques have been developed for the determination of quantitative plasma phenytoin levels.336 Other 5,5- and/or N-l,N-3-disubstituted hydantoin derivatives have been prepared and tested in order to improve and expand the anticonvulsant activity as well as to prevent side effects.Z'*337-340 Significant antiarrythmic activity has been found in certain piperidinespir~hydantoins.~~'-~~~ Recently, antidiabetic activity has been reported for some spirohydantoins. Thus compounds of type 138-145 are potent inhibitors of aldose reductase activity and sorbitol accumulation, being particularly useful in treatment of chronic diabetic complication^.^^'^^^ A. Spinks and W. S.Waring, Prog. Med. Chem. 3,313(1963). H. H.Merrit and T. J. Putman, JAMA, J. Am. Med. Assoc. 111,1068(1938). 334 S.Bogoch and J. Dreyfus, "The Broad Range of Use of Diphenylhydantoin." Dreyfus Medical Foundation, New York, 1970. 335 J. K. Perry and M. E. Newmark, Ann. Intern. Med. 89,207(1979). 336 P. A. Schwartz, C. T. Rodes, and J. W . Cooper, J . Phnrm. Sci. 66(7),994 (1977). 337 R. Eberhad, W. Persch, and A. Schmidt, Arzneim.-Forsch. 5,357(1955). 338 W. Stumpf and K. Rombusch, German Patent 1,173,102(1964)[ C A 61,9504(1964)l. 339 M.A. Davis, S. 0. Winthrop, R. A. Thomas, F. Hen, M.P. Charest, and R. Gandry, J . Med. Chem. 7(4),439 (1964). 340 H. Arnold, E. Kuehas, and N. Brock, German Patent 1,135,915(1962)[ C A 58,3440(1963)J C. Casagrande, A. Galli, R. Ferrini, G. Miragoli, and G. Ferrari, Farmaco, Ed. Sci. 29, 757 332 333

(1974). 343

A. Garcia-Sacristan, M.Illera, and F. Sanz, Arch. Pharmacol. Toxicol. 3(l), 57 (1977). M. R. Martinez-LarraRaga, A. Anadon, and F. Sanz, Arch. Pharmacol. Toxicol. 3(3), 247

(1977). R. Sarges, U.S.Patent 4,130,714(1978)[ C A 92,94401 (1980)l. 34' M. J. Peterson, R. Sarges, C. E. Aldinger, and D. P. MacDonald, Metab., Clin. Exp. 28,456 (1979). 346 R. Sarges, US.Patent 4,286,098(1981)[ C A 95,203958(1981)l. 347 R. Sarges and R. C. Schnur, US.Patent 4,127,665(1978)[ C A 90,87464(1979)l. 348 R. P. Kelbaugh and R. Sarges, U.S. Patent 4,147,797(1978)[ C A 91,20511 (1979)l: 349 D. R. Brittain and R. Wood, European Patent Appl. 28,906(1981)[ C A 95, 150660(1981)l. 350 R. Sarges and R. C. Schmur, U.S.Patent 4,248,882(1981)[CA 94,192339(1981)l. R. Sarges, US.Patent 4,235,911(1980)[CA 94,122540(1981)]. 352 R. C. Schnur. U.S. Patent 4,176,185(1979)[ C A 92, 111015(1980)l. 344

c. AVENDARO L ~ P E ZAND G. GONZALEZ

226

TRIGO

[Sec. V.A

qo HN

0J-4H

Cl

x =o,s 0

Y-NH

Z'

R 3

R2&

NH

R'

I

R

R (144)

( 145)

Some hydantoins are very useful carriers of the nitrogen mustard bis(Pchloroethyl)amine, being active on central nervous system tumors, B 16 melanocarcinoma, leukemia L 1210, leukemia P388, Lewis lung carcinoma, and e pe ndym obla~ toma.~ The ~ ~response of 9L tumor cells in v i m to N-3bis(~-chloroethyl)aminoethylcyclohexanespiro-5'-hydantoinhas suggested its utility in multiagent therapy regimens.354

"'G . Peng, V. Marquez, and J. S. Driscoll, J. Med. Chem. 18(8), 846 (1975). 3s4

F. D. Deen, T. Hoshino, M. E. Williams, K. Nomura, and P. M. Bartle, Cancer Res. 39(1 I), 4336 (1979).

Sec. V.B]

HYDANTOINS

227

Hydantoins and other imidazole analogues of prostaglandins of type 146 and 147 have been synthesized as racemic compounds.355 The less polar diastereoisomer of 146b is a potent inhibitor of platelet aggregation in human platelet-rich plasma.

a R=H

b R=OH c R=O

B. OTHERUSES Hydantoins, thiohydantoins, and their substituted products are particularly useful as catalysts and as stabilizer agents in polymer chemistry and also in the preparation of epoxy resin^.^^^.^^' Thus hydantoins 148 are readily hardened, giving suitable polymers for the preparation of molding and lacquers.

axo

CHZCHzZCH2CH-CHZ ‘0’

I

CHZCHZZCHZCH-CHZ ‘ 0 ’

z =coo,0

N-Trihalomethylsulfenylhydantoins exhibit fungicidal a ~ t i v i t y . ~ ~ * * ~ ~ ~ Other derivatives are herbicides.360

”’A. G. Caldwell, C:J.

Harris, R. Stepney, and N. Whittaker, J.C.S. Perkin I , 495 (1980). D. Porret, Makromol. Chem. 108,73 (1967). u7E. H. Catsiff, R. E. Coulehan, J. F. DiPrima, D. A. Gordon, and R. Seltzer, Org. Coat. Plust. Chem. 39,139 (1978). C. J. Mappes, E.-H. Pornmer, C. Rentzea, and B. Zeeh, US. Patent 4,198,423(1980) [CA 93, 71784 (1980)l. 3 5 9 E. Klauke, E. Kuehle and F. Gravem, Belgian Patent 631,731 (1963) [CA 61, 1873 (19641. 360 H. Ohta, T. Jikihara, KO. Wakabayashi, and T. Fujita, Pestic. Biochem. Physiol. 14,153 (1980). 3s6

228

C. AVENDARO L6PEZ A N D G. GONZALEZ TRIG0

[SeC. V.B

Hydantoins and thiohydantoins have been used as analytical reagents for heavy metals because of their capacity for complex f o r ~ n a t i o n . ~ ~ ~ - ~ ~ ~ ACKNOWLEDGMENT We express sincere thanks to Dr. J. Elguero for his advice and guidelines and to Dr. P. Ballesteros for her comments and criticism.

361

M. J. Blais, 0.Enea, and G. Berthon, Thermochim. Acta 30.45 (1979).

363

M. T. MontaiIa and J. L. Comez-Ariza, Microchem. J . 25,360 (1980).

"'F. Barragan, M. T. Montafia, and J. L. Gomez-Ariza, Microchem. J . 25,524 (1980).

ADVANCES IN HETEROCYCLIC CHEMISTRY. VOL. 38

Recent Progress in Barbituric Acid Chemistry JACEK T. BOJARSKI. JERZY L. MOKROSZ. HENRYK J . BARTON. AND MARIA H. PALUCHOWSKA Department of Organic Chemistry. Nicolaus Copernicus Academy of Medicine. Krakdw. Poland

I. Introduction . . . . . . . . . . . . . . . . . . I1. Physicochemical Properties of Barbiturates . . . . . . A. TautomerismandSolvationof theBarbituric Acid Ring . B. Spectral Properties . . . . . . . . . . . . . . . 1 . UVSpectra . . . . . . . . . . . . . . . . 2. Infrared and Raman Spectroscopy . . . . . . . 3. 'H-NMR Spectroscopy . . . . . . . . . . . 4. I3C-NMR Spectroscopy . . . . . . . . . . . 5. Mass Spectrometry . . . . . . . . . . . . . C Structure and Conformation . . . . . . . . . . 1 . Structure and Conformation in the Solid State . . . a Hydrogen Bonding and Polymorphism . . . . b . Ring Conformations . . . . . . . . . . . c. Orientation of Substituents . . . . . . . . . 2. Conformation in Solution . . . . . . . . . . D. Optical Isomers . . . . . . . . . . . . . . . . 111. Reactivity of Barbiturates . . . . . . . . . . . . . . A. Reactions at the C-5 Atom . . . . . . . . . . . B. Substitution at Nitrogen . . . . . . . . . . . . . C . Reactions of Carbonyl Groups . . . . . . . . . D. Stability of the Pyrimidine Ring . . . . . . . . . E. Photochemical Reactions . . . . . . . . . . . F. Other Reactions . . . . . . . . . . . . . . . IV. Analytical Methods for Barbiturates . . . . . . . . . V . Correlation Analysis in Barbituric Acid Chemistry . . . . VI. ClosingRemarks . . . . . . . . . . . . . . . . . VII. Addendum . . . . . . . . . . . . . . . . . . .

.

.

. . . . . . .

229 231 . 231 236 236 . 240 . 241 . 243 246 . 252 . 252 . 252 . 255 . 255 . 257 259 263 . 263 269 . 273 . 276 . 282 283 . 288 . 292 295 297

. . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

.

.

. . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.

I Introduction The chemistry of barbituric acid and its derivatives has been studied for over 100 years if we consider 1864. the year the parent compound of this class was prepared by von Baeyer. as its starting point . In 1903 the therapeutic

' A. von Baeyer. Ann. Chem. Pharm. 130. 129 (1864). 229

Copyright 0 1985 by Academic Press. Inc. All rights of reproduction in any form reserved. ISBN 0-12420638-2

230

[Sec. I

JACEK T. BOJARSKI et a/.

value of 5,5-diethylbarbituric acid (barbital) as a hypnotic agent was reported by Fisher and von Mering* and since that time constant progress in chemical and pharmacological studies on barbiturates has been observed and reported. Several earlier review articles are cited in the fundamental work of Doran in 1959.3 This book provides general information on the chemistry and pharmacology of barbiturates, but its main value lies in a compilation of an extensive bibliography on the preparation and pharmacological activity of these compounds. More details on synthesis, properties, and reactivity are provided in the review by Levina and Velichko in 1960.4Since that time further studies dealing with structure and conformation, spectral properties, and structure-activity relationships have been among the main advances in barbiturate chemistry. These topics were reviewed by Bobranski.' This review presents the most important recent information on barbituric acids with special emphasis on their physicochemical properties. Although barbituric acid [2,4,6-( lH,3H,SH)-pyrimidinetrione] (1) and its derivatives now are listed in Chemical Abstracts by their IUPAC names, there is a well-established tradition to use the name "barbituric acid" along with prefixes denoting appropriate substitution. This system was used in Chemical Abstracts until 1972; we adopt it for convenience. The terms barbituric acid and barbiturates are used interchangeably for a general description of derivatives of 1, while the subclasses and individual compounds are named according to the mode of substitution, e.g., 5,5acid (3). dialkylbarbituric acids (2) or 5-ethyl- 1-methyl-5-phenylbarbituric Several barbiturates of therapeutic importance have common names or names adopted by manufacturers but we will use only their recommended international nonproprietary names [e.g., methylphenobarbital (3)].6

HL "'P/N o \" .g;:-.- :LkH no

R

I

O

0

I

"O

"O

0

0

E. Fisher and J. R. von Mering, Ther. Ggw. 44,97 (1903).

' W. J. Doran, Med. Chem. 4, 1 (1 959).

R. Ya. Levina and F. K. Velichko, Russ. Chem. Rev. (Engl. Transl.)29,437 (1960). 9. Bobranski, W a d . Chem. 31,231 (1977). M. Negwer, "Organic-chemical Drugs and their Synonyms." Akademie-Verlag, Berlin, 1978.

Sec. I I . A ]

23 1

BARBITURIC ACID

11. Physicochemical Properties of Barbiturates

A. TAUTOMERISM AND SOLVATION OF THE BARBITURIC ACIDRING Barbituric acid exists in the solid state in the trioxo structure as shown by Xray7**and 14N-NQR9 methods. NMR investigation of the 0x0-hydroxy equilibrium also indicates that only the 0x0 form is present in a solution in anhydrous DMSO."*'' The hydroxy form (4b) appears in a water-free acid .'~ methods" and UV but the 0x0 form (4a)is still p r e d ~ m i n a n t . ' ~ Relaxation rneas~rements'~ give pKT = 1.9 and 1.3, respectively, for 4a/4b in water, and substitution at the nitrogen atoms (N-methyl- and N,N'-dimethylbarbituric acid) has no influence on pKT (1.65 and 1.83, respectively). Introduction of substituents in the 5-position results in the predominance of the hydroxy form, pKT being 0.88,0.76, and 0.21, respectively, for Me, C1, and Br; results can be explained by inductive effects.13 The 0x0 form dominates in aprotic solvents. H

I

N y I

:J&

H

I

-H:&T; K,

0

0

(40)

(4b)

In amphiprotic solvents, the amount of the 0x0 form decreases, and in protondonating solvents it increases again. IR spectra of barbituric and 5chlorobarbituric acids in the solid state and in solution are consistent with those re~u1ts.l~ X-ray and IR analyses show that 1,3-diethylbarbituric acid exists in the trioxo form, while its sulfur analogue is in the monohydroxy form in the solid.' Generally, 5,5-di- and 1,5,5-trialkyl, -alkenyl or -aryl substituted barbiturates have the trioxo form in the crystalline state. Included are

' G . A. Jeffrey, S. Chose, and J. 0.Warwicker, Acra Crystallogr. 14,881(1961). W. Bolton, Acta Crystallogr. 16, 166 (1963). T. Maruizumi, Y.Hiyama, and E. Niki, Bull. Chem. Soc. Jpn. 53,1443 (1980). l o G.A. Neville and D. Cook, Can. J . Chem. 47,743(1969). I ' J. A. Glasel, Org. Magn. Reson. 1,481 (1969). I 2 M.Eigen, G. Ilgenfritz, and W. Kruse, Chem. Ber. 98, 1623 (1965). l 3 W.I. Slesarev and B. A. Ivin, Zh. Org. Khim. 10, 113 (1974). l4 N.A. Smorygo and B. A. Ivin, Khim. Geterotsikl. Soedin., 1411 (1975). J.-P. Bideau, P. V. Huong, and T. Toure, Acta Crystallogr., Sect. B B32,481(1976).

''

232

JACEK T. BOJARSKI et al.

[Sec. 1I.A

5,5-diethyl-,16 5-ethyl-5-(l’-methylb~tenyl)-,~’ 5-methyl-5-phenyl-,’* l-methyl5-ethyl-5-phenyl-,19 or l-(p-bromophenyl)-5,5-diallylbarbituricacid20 (see also references in Section II,C,l), In the solid state, however, monopotassium salts exist in the dioxo structure, which is confirmed by X-ray2’ and IR investigations.22 Moreover, there are no indications of the presence of the hydroxy form in the ‘H-NMR spectra of the 5,5-disubstituted barbiturates in CF,COOH, p-dioxane, or DMSO.” IR results show that for 5-alkyl-5-a- and 5-fi-alkoxyethylbarbiturates in solution the 0x0-hydroxy equilibrium depends on the inductive effect of substituents, i.e., 5-a-alkoxyethyl substituents shift the equilibrium toward the hydroxy form.23 In the solid state and in aprotic solvents, 5-benzylidenebarbituric acid and its meta- and para-substituted derivatives (5) also have the trioxo structure, according to their ‘H-NMR, IR, and UV spectra.24 H

(5)

1,5,5-Trisubstituted barbituric acids (6) exist in the hydrogen-bonded, monohydroxy form in the solid state, as revealed by a comparison of IR spectra. 1,3,5,5-Tetrasubstituted derivative 7, which cannot form an intramolecular hydrogen bond, was used as a

B. M. Craven, E. A. Vizzini, and M. M. Rodrigues, Acta Crystallogr., Sect. B 825,1978(1969). B. M. Craven and C. Cusatis, Acta Crystallogr., Sect. B B25.2291 (1969). G. Bravic, J. Housty, and J. P. Bideau, C . R. Hebd. Seances Acad. Sci., Ser. C 266,969 (1968). ” J.-P. Bideau, L. Marly, and J. Housty, C . R. Hebd. Seances Acad. Sci., Ser. C 269,549 (1969). 2o D. Pyhlska, R. Pytalski, and T. Borowiak, Acta Crystallogr., Sect. B B36, 1672 (1980). J. Berthon, B. RCrat, and C. RCrat, Acta Crystallogr. 18,768(1965). 22 C. F. Gavrilin, V. E. Chistyakov, and G. A. Kononenko, Zh. Obshch. Khim. 40,669(1970). ” A. V. Bogatskii, G. Y.Glinskaya, and A. I. Gren, Zh. Obshch. Khim. 39,2568 (1969). 24 B. A. Ivin, A. I. Dyachkov, I. M. Vishnyakov, N. A. Smorygo, and E. G. Sochilin, Zh. Org. Khim. 11, 1337 (1975). 2 3 H. J. Roth, K. Jager, and R. Brandes, Arch. Pharm. (Weinheim, Ger.) 298,885(1965). l6

I’

*’

Sec. II.A]

233

BARBITURIC ACID

1,3-Disubstituted-5-acylderivatives of barbituric acid (8a) enolize with the aid of the 5-b carbonyl group. Formation of an intramolecular hydrogen bond with the carbonyl group at C-4 or C-6 gives 8b, and then proton transfer leads to the monohydroxy form &, as demonstrated by 'H-NMR and UV studies.26

Anhydrous 5-nitrobarbituric acid (9) exists in the monohydroxy form but the trihydrate is in the aci-nitro form (9b)28in the crystalline state as shown by X-ray analysis. IR and UV investigation^^^ and dipole moment measurementsJo are consistent with those conclusions. The results of M O calculations show that the monohydroxy structure (9a)is the most stable. UV spectra3' as well as 14N-NQR dataJ2also support tautomer 9a in water. H I

Y

OH

(93

0-

0 (ob)

Crystal data show that dialuric acid (10)exists in the dihydroxydioxo form (10b),33*34 but 'H-NMR studies of DMSO solutions suggest the existence of a monohydroxytrioxo structure (lOa)." N o evidence of tautomerism is

K. Rehse and W.-D. Kapp, Arch. Pharm. (Weinhim, Cer.)315, 502 (1982). W. Bolton, Acta Crystallogr. 16,950 (1963). 28 B. M. Craven, S. Martinez-Camera, and G . A. Jeffrey, Acta Crystallogr. 17,891 (1964). 29 F. Mihai and R. Nutiu, Reo. Roum. Chim. 13,39 (1968). 30 R. Nutiu, L. Kurunczi, and Z. Simon, Rev. Roum. Chim. 14, 1435 (1969). " Z. Simon, F. Mihai, and R. Nutiu, Reo. Roum. Chim. 13,147 (1968). 32 S. N. Subbarao and P. J. Bray, J . Chem. Phys. 67,1085 (1977). 33 W. Bolton, Acta Crystallogr. 19, 1051 (1965). 34 B. M. Craven and T. M. Sabine, Acta Crystallogr., Sect. B B25, 1970 (1969).

26

27

234

JACEK T.BOJARSKI

[Sec. I1.A

et al.

observed for 5,5-dihydroxybarbituric acid (11) from X - r a ~ ,'H-NMR,' ~ ~ , ~ ~ and 14N-NQR9investigations. H

I

O&YO N, H

HO

HO 0

(nI In aqueous solution the hydroxy forms of barbituric acids are in equilibrium with their mono- and dianionic conjugate bases (Scheme 1). The acidbase equilibria are strongly dependent on the site of substitution and the nature of the s u b ~ t i t u e n t s ~ '(Table - ~ ~ I).

(12b)

1-

2-

SCHEME1

Resonance and large inductive effects of substituents easily account foi changes in pK, values, but small changes are more difficult to interpret.' 3*40*43 Monoanions 12b and 13b are 104-108times weaker acids than their neutral conjugate acids. The influence of electronic effects of substituents on the

Sec. ILA]

235

BARBITURIC ACID TABLE I INFLUENCE OF SUBSTITUTION ON pKa, AND

Barbituric acid

5-Ch1oro 5-Bromo 5-Phenyl 5-Alkyl Unsubstituted 1-Methyl 5lEthyl-5-phenyl 5-Ethyl-5-alkenyl 5,SDialkyl l-Methyl-5,5-disubstituted 5,SAlkylene

pKa, OF BARBITURATES

PK.,

References

0.00 0.t6 2.54 3.4-4.9 4.10 4.35 7.41 7.4-8.0 7.8-8.5 7.9-8.8 8.7-8.9

13 13 38 37,38 13,37 13 13,39 11,38,40 39-43 40.41 44,45

PK,,

References

12.60 12.90 12.14 12.2-12.7 12.4-12.8

13 13 40 40

40

second step of ionization is less clear, owing to fewer studies. Acid strength is almost independent of the length of the straight-chain alkyl group attached to the C-5 atom of the ring, e.g., ApK,, = 0.07 for 5-ethyl-5-n-pentyl- and $5diethylbarbituric acids. Introduction of a methyl group in the a position of an alkyl chain at C-5 increases the pK,, by about 0.2 unit, while the introduction of a methyl group at the fl or y carbon atom causes either a very slight decrease in the pK,, (-0.06 unit) or has no significant effect.3942 Replacement of the ethyl substituent at C-5 by a methyl group results in a small acid-weakening effect and pK,, values are higher by about 0.3.40-4’-4346 Large alkyl groups at the C-5 position shield the C-4 and C-6 carbonyl groups and hinder ~ o l v a t i o nOn . ~ the ~ ~other hand, an increase in the ionic strength of the solvent results in a decrease of pK,,, followed by stronger solvation, for 5,5-disubstituted barbiturate^.^' A comparison of the pK,, values for 5,Sdiethylbarbituric acid (8.00 k 0.02) and its spirocyclic derivatives (14) (n = 4 and 5; pK,, = 8.83 and 8.88, ” D.

Mootz and G . A. Jeffrey, Acta Crystallogr. 19,717 (1965). C. Singh, Acta Crystallogr. 19,759 (1965). 37 W. F. Smyth, T. Jenkins, J. Siekiera, and A. Baydar, Anal. Chim. Acta 80,233 (1975). ” H. Koffer, J.C.S. Perkin 11, 1429 (1974). 39 M. E. Krahl, J . Phys. Chem. 44,449 (1940). 40 D. A. Doornbos and R. A. de Zeeuw, Pharm. Weekbl. 104,233 (1969). 4 1 D. A. Doornbos and R. A. de Zeeuw, Pharm. Weekbl. 106 134 (1971). J. M. A. Sitsen and J. A. Fresen, Pharm. Weekbl. 108, 1053 (1973). 43 R. H. McKeown, J.C.S. Perkin 11,504 (1980). 44 R. H. McKeown and R. J. Prankerd, J.C.S. Perkin 11,481 (1981). ” R. H. McKeown, J.C.S. Perkin I I , 515 (1980). 46 J. Mokrosz and J. Bojarski, Pol. J . Chem. 56,491 (1982). 36

236

JACEK T. BOJARSKI et a[.

[Sec. 1I.B

respectively) shows significant influence of the substituent with almost the same electronic nature but different shielding effect on solvation and acidity of these compounds. However, 5,S-dimethylbarbituric acid, where the steric effect of methyl groups should be similar to that in compounds 14, has a pK,, = 8.5 1. This acid-strengthening effect is explained by the hyperconjugative effect of methyl g r o ~ p s . 4 ~ ~ ~ ~ The acidity of 5-methyl- and 5-ethylbarbituric acids is slightly greater than that of barbituric acid (pK,, = 3.39,3.69, and 4.02, respectively), a conclusion

Y

In)

not expected from a consideration of the usual inductive electron-donating effect of alkyl groups.38 Relaxation methods show that the influence of substituents on individual reaction rate constants among 0x0, hydroxy, and anion forms is responsible for the unusual acidity of these corn pound^.^' Further studies on the acid-base equilibria of 5,5-biscarboxymethyl-,4*5az0-,4’ and 5-ylidenebarbit~rates~~*’~ are also available.

B. SPECTRAL PROPERTIES 1. UV Spectra

Near-UV absorption spectra of barbiturates depend on the type of substitution and the state of ionization of the m o l e c ~ l e . ~Absorption ~-~~ bands at -210 nm for undissociated compounds are shifted to 240-270 nm

H. KofTer. J.C.S. Perkin !I, 819(1975). J. Mirek, M. Adamczyk, and P. Krol, Chem. Anal. 24,739 (1979). 49 V. Madajova and J. Zelensky, Collect. Czech. Chem. Commun.46,987 (1981). so P. Schuster and 0.E. Polansky, Monatsh. Chem. 99,1234 (1968). 5 1 R. Bednar, 0.E. Polansky, and P. Wolschann, Z . Naturjorsch., B: Anorg. Chem., Urg. Chem. 4’

30B,582 (1975). J. Fox and D. Shugar, Bull. Soc. Chim. Belg. 61.44 (1952). ” L. A. Gifford, W. P. Hayes, L. A. King, J. N. Miller, D. T. Bums, and J. W. Bridges, Anal.

” J.

Chem. 46,94 (1974). J. Berdnikov and S. P. Bystrov, Farmatsip 25,32 (1976).

” A.

Sec. II.B]

237

BARBITURICACID

10.5 10

8

0

?

6

X

w

4

l-\k

2

.

220

210

230

240

250

260

270

280

FIG.1. UV spectra of 5,5-diethylbarbituricacid at various pH values.

-

for ionized forms (Fig. 1). Monoionized forms (Scheme 1) exhibit the highest absorption intensity ( E lo4). Substitution at the nitrogen and C-5 atoms results in a slight bathochromic shift and a decrease in inten~ity.~’ UVabsorption spectra of barbiturates with the same substitution and ionization modes are independent of the kind of s u b s t i t ~ e n t s ~(Table ~ - ~ ~ 11). Calculations by the PCILO method agreed with that conclusion and indicated that neither the chemical structure nor the conformational aspects of the substituents attached to C-5 exert a significant perturbation on the groundstate electronic charge distributions in the barbituric acid ring.” On the contrary, for 2-thi0-~’and 5-ylidenebarbituratesZ4a significant bathochromic shift and an increase in intensity of absorption bands are observed (Table 11). ” G.

Milch and 1. Vagi, Lwnin.-Spektroszk. Kut. Alkamazasi Probl. Magy. Tud. Akad. Spektroszk. Albizottsaga, 173 (1979)[ C A 95,153398(1981)l. ” C. I. Miles and G. H. Schenk, Anal. Chem. 45, 130 (1973). ” H.Barton and J. Bojarski, Pharmazie 38,630(1983). ” J. Mokrosz, M. Klimnak, H. Barton, and J. Bojarski. Pharmazie 35,205(1980). 59 B. Pullman, J. L. Coubeils, and P. Courriere, J . Theor. Biol. 35,375(1972). 6o 2.Kazimierczuk, A. Psoda, and D. Shugar, Acta Biochim. Pol. 20,83(1973).

238

[Sec. 1I.B

JACEK T. BOJARSKI et 01.

TABLE I1 uv PARAMETERS OF BARBITURATE^ IN BUFFERS ~ L U T I OFOR N SUNDISOCIATED (A), TYPICAL MONOANIONIC (B). A N D DIANIONIC (C) FORMS~

B Position ofsubstitution None 5 5.5 155 1.3.5.5 1 1,3

5,5-,2-Thio 5-Benzylidened

(I

A,, (nm)

E

x lo-’

I,,,,,(nm)

ima, (nm) t; x

10.4

257.5

-

-

212.5 222.5 228-230 219.5 226 285 230-250 3 15-452

9.15 7.95 6.3- 10.0 8.7 7.9 24 8.0- 15.0 17.0-40.5

263-271 239-241 245-246

205

C

258.5 260 305

21.5’ 19.8‘ 17.1-21.6 9.3- 10.6 8.5-8.7 20.3

260 -

255-256 -

f:

lo-’

x

15.2‘ 15.1‘ -

6.8-7.95 -

-

-

260

1r.9

-

15.0 _-

26

306

28

-

-

Data from refs. 24, 52, 53, 57, 58, 60. From reference 52. From reference 53. Dioxane solution.

Luminescence spectra of barbiturates have been studied, usually for analytical purposes by room-53*61-65or low-temperature (77 K) techn i q u e ~ . The ~ ~ structure-luminescence ~ ~ ~ ~ ~ ~ - ~ ~ relationship^^^*^^ and the influence of substituents on the fluorescence characteristics were also i n v e ~ t i g a t e d . ~ ~ *Only ~ ~ - ”5,5-disubstituted barbiturates, as the dianion species, show significant fluorescence at 420 nm. However, the dianions of other barbiturates exhibit very weak emissions or none at all, except for 5phenylbarbituric acid.s3 Barbiturates also exhibit low-temperature fluS. Udenfriend, D. E. Duggan, B. M. Vasta, and B. B. Brodie, J. Pharmacol. E x p . Ther. 120,26 (1957). 62 J. E. Swagzdis and T. L. Flanagan, Anal. Biochem. 7 , 147 (1964). 63 P. G. Dayton, J. M. Perel, M. A. Langrau, L. Brand, and L. C. Mark, Biochem. Pharmacol. 16, 2321 (1967). 64 C. 1. Miles and G. H. Schenk, Anal. Lett. 4.61 (1971). ” L. A. King, J. N. Miller, and D. T. Burns, Anal. Chim. Acta 68,205 (1974). 66 L. A. Gifford, W. P. Hayes, L. A. King, J. N. Miller, D. T. Burns, and J. W. Bridges, Anal. Chim.Acta 62,214 (1972). 6 7 J. D. Winefordner and M. Tin, Anal. Chim. Acta 32,64 (1965). 68 L. A. King and L.A. Gifford, Anal. Chem. 47, 17 (1975). 69 L. J. Cline-Love and L. M. Upton, Spectrochim. Acta, Part A 37A,879 (1981). ’O L. A. King, J.C.S. Perkin II,844(1976). ” L. A. King, J.C.S. Perkin 11, 1725 (1976). 6’

Sec. II.B]

BARBITURIC ACID

239

orescence at 77 K, but slight blue shifts were observed.53 Those with unsaturated substituents at C-5 show very weak fluorescence, but 5-phenyl derivatives exhibit strong phosphorescence near 400 nm with lifetimes of several s ~ c o ~ ~ s This . ~ long-lived ~ ’ ~ ~ emission * ~ ~ is* maintained ~ ~ even in acidic media, except for 5-phenyl- and 5-benzylbarbituric acids. King proposed that phosphorescence is derived from phenyl because of intramolecular energy tran~fer,~’ whereas the pyrimidine ring is responsible for fluore~cence.~~ The effect of C-5 substituents on the relative fluorescence quantum yields was explained by King in terms of the inductive effect.68 Cline-Love and Upton found microsecond natural lifetimes for $5disubstituted barbiturate^.^^ This suggests that the fluorescence transition is of the n + n* type, although the absorption should be of the n -+ n* type. Moreover, natural lifetimes of the excited states for barbiturates with unsaturated substituents are longer than those for barbiturates with alkyl groups. A small mixing of electronic levels of the fluorophore with the levels of the electronic environment provided by the unsaturated substituents have been proposed to explain this p h e n ~ m e n o n . ~ ~ The electronic structure of barbiturates has also been investigated by spectropolarimetric Circular dichroism (CD) spectra of a series acids show three Cotton effects centered of (S)-5-alkyl-5-(2’-pentyl)barbituric around 212,240, and 260 nm, and the short-wavelength band is positive and has an opposite sign in relation to the longer wavelengths. However, in the case of (S)-5-(2’-pentyl)barbituricacid, the signs of all three Cotton effects are opposite to those of all the other derivatives. The solvent studies indicate that the 212- and 260-nm bands arise from the n -+ n* and n -+ n* transitions, respectively, but the 240-nm band is due to n -,CT* or the second n + n* transition^.^^ An influence of concentration and ionization mode has not been observed. Similar assignment of three Cotton effects has been reported for (S)5-alkyl-5-(2’-pentyl)-2-thiobarbituric Both experimental data73.75and theoretical calculations7* show that differences in the sign of the Cotton effects of 5-mOnO- and 5,5-disubstituted barbiturates are sensitive to chiral distortions within the barbituric acid ring. The induced C D spectra of barbiturates as inclusion complexes with Bcyclodextrin support the foregoing conclusion. 79

’* L. A. King, Spectrochim. Acta, Part A 31A, 1933 (1975). 73 F. I. Carroll and R. Meck, J. Org. Chem. 34,2676 (1969). ’‘ F. I. Carroll and A. Sobti, J: Am. Chem. SOC.95,8512 (1973). ” F.

I. Carroll, A. Philip, and C. G . Moreland, J. Med. Chem. 19,521 (1976). F. I. Carroll, D. Smith, G . N. Mitchell, and A. Sobti, J.C.S. Perkin 11,983 (1977). J. Knabe and W. Wunn, Arch. Pharm. (Weinheim, Ger.)315,977 (1982). C. Y. Yeh and F. S. Richardson, Theor. Chim. Acta 39, 197 (1975). ” M. Otagiri, T. Miyaji, K. Uekama, and K. Ikeda, Chem. Pharm. Bull. 24,1146 (1976). 76

’’

240

JACEK T. BOJARSKl et a/.

[Sec. 1I.B

A number of the CD spectra of barbituric acid derivatives were also reported by Knabe and co-workers” (see also references in Section 11,D).

2. Infrared and Raman Spectroscopy The main purpose of the IR and Raman analysis has been the detection and identification of particular derivatives as the free acid, their salts, or metal comple~es.~’-~’ Although detailed interpretation of the spectra largely concerned only the N-H and C=O stretching modes, even for these regions there were some controversies about the origin of the peaks.”-” Two bands of the N-H stretching vibration (at 3200 and 3090 cm-’) are observed in the IR spectra of barbituric acid and its derivatives in the solid ~ t a t e . ~ ’ * ~The ’-~~ position and intensity of these bands depend on the degree of the hydrogen b ~ n d i n g . ~ ~ . ~Ho ’ - ’wever, ~ in highly dilute solutions and in argon matrices, a strong vibration at -3400 cm-’ and two broad bands in the region 32503100 cm-’ are observed, which correspond to the monomeric and dimeric forms, respe~tively.~’-~~*~’-~~ In the IR spectra between 1770 and 1680 cm-’, three bands of the C=O modes are observed. Analysis of IR and Raman spectra of four barbiturates in low-temperature matrices showed that the highest frequency band is attributable to the 4,6-C0 symmetric vibration, the middle to the 4,6-C0 antisymmetric stretch, and the lowest frequency band to the 2-CO mode92-94 J. Knabe, H. Junginger, and W. Geismar, Justus Leibigs Ann. Chem. 739.15 (1970). W. C. Price, J. E. S.Bradley, R. D. B. Fraser, and J. P. Quilliam, J. Pharm. Pharmacol. 6,522 (1954). L. Levi and C. E. Hubley, Anal. Chem. 28,1591 (1956). 8 3 J. M. Manson and J. A. R.Cloutier, Appl. Spectrosc. 15, 77 (1961). 84 S.Goenechea, Z . Anal. Chem. 218,416 (1966). .3’ S. Pinchas, Spectrochim. Acta 22,1889 (1966). 86 R. BouchC, L. Coclers, R. Delahaut, and J. Muquardt, J . Pharm. Belg., 282 (1970). ” A. Sucharda-Sobczyk, Rocz. Chem. 41,1435 (1970). M. Kuhnert-Brandstatter and F. Bachleitner-Hofmann. Arch. Pharm. (Weinheim, Ger.) 304, 580 (1971). 89 J. N. Willis, R.B. Cook, and R.Jankow, Anal. Chem. 44,1228 (1972). 90 A. Sucharda-Sobczyk, Rocz. Chem. 46,517(1972). 91 D.J. Moffatt and G. A. Neville, Can. J . Spectrosc. 26, 14 (1981). 92 A. J. Barnes, M. A. Stuckey, W.1.Orville-Thomas, L. Le Gall, and J. Lauransan, J . Mol. Struct. 56, 1 (1979). 93 A. J. Barnes, L. Le Gall, and J. Lauransan, J . Mol. Struct. 5 6 , l S (1979). 94 A. J. Barnes, L. Le Gall. and J. Lauransan, J . Mol. Struct. 56,29(1979). 9’ R. J. Mesley, Spectrochim. Acta, Part A 26A, 1427 (1970). 96 K. Hollenbach, J. Meziisi, K. Pintye-Hodi, and G. Kedvessy, Pharmazie 34,240(1979). 97 N.A. Smorygo and B. A. Ivin, Khim. Geterotsikl. Soedin., 1402 (1975). 98 M. Guerin, J. M. Dumas, and C. Sandorfy, Can. J . Chem. 58,2080(1980).

Sec. II.B]

BARBITURIC ACID

24 1

FIG.2. Carbonyl stretching vibrations of barbituric acid ring: (a) 4,6420 symmetric; (b) 4,6CO antisymmetric, (c) 2-CO.

(Fig. 2). Band b is the most sensitive of the carbonyl stretches for conjugation within the pyrimidine ring.87 Raman spectra of barbituric acid could not be obtained because of its high luminescent b a c k r o ~ n d , 9 ~but * ' ~Willis ~ et af. gave interpretations of Raman spectra for eight barbiturate^,^^ and Barnes et al. reported a detailed analysis of IR and Raman spectra for the whole frequency range for 1-methyl-, 1,3dimethyl-, and 5,5-diethylbarbituric Similar IR and Raman spectra analyses were described for 5-ethyl-5-phenylbarbituricacid and its N-monoand N,N-disubstituted derivatives.'" A detailed interpretation of IR spectra of the 1-acyl and 1-(4'-aminobutynyl) derivatives was also r e p ~ r t e d . ' ~ ~ . ' ~ ~

3. 'H-NMR Spectroscopy The 'H-NMR spectroscopy of common, medicinal 5,5-di- and 1,5,5trisubstituted barbiturates is very well described in the literatUre.10,24.26.104-1 10 Chemical shifts of substituents attached to the nitrogen atoms or to the C-5 atom of the barbituric acid ring, together with their multiplicity, completely characterize particular barbituric acid derivatives and serve for identification. 99

loo 'I

Io2

Io4 lo'

lo'

11'

J. R. Nestor and E. R. Lippincott, J. Mol. Spectrosc. 51,351 (1974). L. Le Gall and A. J. Barnes, Ber. Bunsenges. Phys. Chem. 82,52 (1978). R. Buchet, H. Bill, and B. Siegfried, Spectrochirn. Acta, Part A %A, 239 (1982). A. Sucharda-Sobczyk and J. Bojarski, Rocz. Chem. 44,2333 (1970). B. Danielsson, Acta Pharm. Suec. 2,47 (1965). G. Rucker, Arch. Pharm. (Weinheim, Ger.)299,688 (1966). H. W. Avdovich and G. A. Neville, Can. J . Pharm. Sci. 4,51 (1969): H. Lackner and G. Doring, Arch. Toxicol. 26,237 (1970). G. A. Neville, H.W.Avdovich, and A. W. By, Can. J . Chem. 48,2274 (1970). E. L. Frochaux-Zeidler and B. Testa, Pharm. Acta Helu. 54,229 (1979). P.R. Andrews, A. J. Jones, G. P. Jones, A. Marker, and E. A. Owen, Eur. J. Med. Chem.Chim. Ther. 16,145 (1981). M.Yogo, K. Hirota, and S. Senda, Chem. Pharm. Bull. 30,1333 (1982).

242

[Sec. 1I.B

JACEK T. BOJARSKI el al. TABLE 111 CHEMICAL SHIFTS OF THE NH PROTONS FOR 5,5-DI- AND I ,5,5-TRISUBSTITUTED BARBITURATES

6," (ppm)" in different solvents Barbituric acid derivative 5-All yl-S-cyclopenten yl 5-Allyl-5-phenyl l-Methyl-5-(2'-bromallyl)5-isopropyl 5,SDiethyl l-Methyl-5,5-diethyl 5-Ethyl-5-isopropyl 5-Ethyl-5-phen yl I-Methyl-5-ethyl-5-phenyl

CDCI,

p-Dioxane

DMSO-d,

-

10.0 9.7

11.4 11.6

10.2 10.1 10.1 10.0 10.2 10.2

11.7 11.4 11.6 11.3 11.7 11.9

9.1 9.4 9.4 -

8.7 8.8

Chemical shift 6 in ppm versus TMS.

Electronic effects of substituents at the C-5 position influence the chemical shift of the NH protons in 5,5-di- and 1,5,5-trisubstituted derivatives, and the possibility of an interaction of the barbituric acid nucleus with a solvent, usually through a hydrogen bond, was confirmed by NH chemical shifts as shown in Table 111. One of the imide protons (NH) of the barbituric acid ring engages in intermolecular hydrogen bonding with DMSO or N,N-dimethylacetamide.'0*'07*''' The formation of the intramolecular hydrogen bond in 5hydroxy-l,3,5-triethylbarbituric acid (15) causes different chemical shifts of the N-1 and N-3 ethyl groups owing to the anisotropic effect of the C-4and C 6 carbonyl groups.'"

?

(15)

(%)

Two resonance signals for N-methyl groups in the spirobarbiturate 16 are also observed as a result of the long-range magnetic effect of the p-nitrophenyl moiety.' l 2 'I'

K. C. Tewari, F. K.Schweighardt, J. Lee, and N. C. Li, J . Magn. Reson. 5,238 (1971). R. Bednar, U. Herzig. I. Schuster, P. Schuster, and P. Wolschann, Org. Magn. Reson. 8, 301 (1976).

Sec. II.B]

BARBITURIC ACID

243

The influence of solvent on the chemical shift of substituents at the 5position was also inve~tigated.'~~~'~'*'~~ Proton-donating solvents result in significant downfield shifts of the resonance of 5-alkyl groups; for example, differences in the chemical shifts of the l'-CH, protons in trifluoroacetic acid and dioxane is 0.3-0.5 ppm.' 04*' O 7 Bobranski explained this phenomenon by suggesting protonation of the barbiturate ring in strong acidic media, which results in the deformation of this ring from planarity and then in deshielding of the 5-substituent protons.'' O n the other hand, Neville and Cook claim that solute-solvent hydrogen-bond interactions are r e s p ~ n s i b l e . 'In ~ ~fact, both may be important. The 'H-NMR spectra of 5-arylidenebarbiturates (17) in DMSO-d6 show, besides aromatic proton signals, two singlets for NH or NMe protons and a singlet for the olefinic proton (Table IV).24.'"*' 14*'

(17)

The differences in chemical shifts of protons a and b are caused by the anisotropy of the C-4 and C-6 carbonyl groups owing to the geometry of 17. But an influence of substitution in the aromatic ring on the chemical shift of the NMe protons is less visible in relation to that for the NH protons (Table IV). 'H-NMR spectra of some barbiturates complexed with lanthanide ions were also investigated.' 6-1 '*

'

4. 13C-NMR Spectroscopy

'

The 3C-NMR spectra of over 100 barbiturates, thiobarbiturates, and arylidenebarbiturates are reported in the literature. Ranges in the chemical shifts of carbon atoms in the barbituric acid nucleus and in NMe groups for different classes of derivatives (18 and 19) are shown in Fig. 3. 'I3

'I4

B. Bobranski, Rocz. Chem. 43, 1971 (1969). R. Bednar, E. Haslinger, U. Herzig, 0.E. Polansky, and P. Wolschann, Monatsh. Chem. 107, 11 15 (1976).

'15 'Id

'I8

E. Haslinger and P. Wolschann, Org. Magn. Reson. 9, 1 (1977). J. Knabe and V. Gradmann, Arch. Pharm. (Weinheim, Ger.)310,468 (1977). J. Triepel and H.-H. Otto, Monatsh. Chem. 108, 1085 (1977). J. Ascenso, M. Candida, T. A. Vaz, and J. J. R. Frausto Da Silva,J. Inorg. Nucl. Chem. 43,1255 (1981).

244

[Sec. I1.B

JACEK T. BOJARSKI et a/. TABLE IV 'H-NMR CHEMICAL SHIFTS OF THE NH, NCH,, AND =CH PROTONS FOR 5-ARYLIDENEBARBITURA~ (17)'

m-OMe p-Br P-NOz H o-NOZ p-OMe p-NMe,

11.52 11.38 11.35 11.29 11.24 1 1.22 11.03

11.69 11.53 11.45 11.39 11.49 11.32 11.16

8.50 8.34 8.40 8.42 8.62 8.42 8.25

3.38 3.36 3.36 3.22 3.24 3.38 3.35

3.49 3.44 3.45 3.28 3.42 3.40 3.36

-

-

8.86 8.47 -

Chemical shift 6 in ppm versus TMS.

B'

8

Differences in the "C chemical shifts of the C-5 atom for compounds of type 18 are dependent on the nature of substituents R' and R2 and amount to -6-11 ppm, while those for C-2, C-4, and C-6 atoms are only 1.5-2.5 4 2 , 7 5 ,119-1 27 PPm. In the 13C-NMR spectra of sodium salts of 5,5-disubstituted derivatives (18) the signals of C-2 and C-4(6) carbonyl groups are shifted downfield by -13 and 10 ppm, respectively, in relation to their undissociated forms.75.109.1

20.123.126

For meta- and para-substituted arylidenebarbiturates (19) the conjugation in the molecule extends from the aromatic moiety over the C-5=C-7 bond to K. Rehse, Dtsch. Apoth.-Zty. 112, 1185(1972). A. Fratiello, M. Mardirossian, and E. Chavez, j . Magn. Reson. 12,221 (1973). l z 1 J. Okada and T. Esaki, Yakugaku Zasshi 93,1014 (1973). 'Iz J. Okada and T. Esaki, Chem. Pharm. Bull. 22, 1580 (1974). lz3 R. C. Long and J. H. Goldstein, J. Magn.Reson. 16,228 (1974). F. I. Carroll and C. G. Moreland, J.C.S. Perkin 11,374 (1974). 12' S. Asada and J. Nishijo, Bull. Chem. SOC.Jpn. 51,3379 (1978). l Z 6 H. W.Avdovich and G. A. Neville, Can. J . Pharm. Sci. 15, 75 (1980). l Z 7 M. Rautio and E. Rahkamaa, Org. Magn. Reson. 15.53 (1981). 119

lZo

-

c-2 8

C-4.6 I

C-k6

-

C-1 I

C-4

-

I

c-2

-

0 C-6

C-4.6

C-S

I

c-5

C-2

C-4

~

c-s

c-2 I

I

I C-6

c-46

C-2

I

I

c-5

c-2

C-46 I

C-2 8

C -5

I

N-Me

I

I

c -4

m

I

N-WC

I

c -5

D

C-6

c-6

r

c-7

-I

I

J

c-0

C-4

-

:.'I

c-6 . .

= c-7

-

K

c-4

-

c-2

I

C-8

I ~ l i i l l l l i l l l 1 l I l l ~l ~

a bpm)

.(80

470

w

450

"

1

I20

1

1

1

1 t(0

1

1 "

1I

l l l ~ l l ~ ~ l l l l ~ l ~ l l 60

50

4a

30

FIG.3. The "C-NMR chemical shifts of barbiturates 18 and 19 in DMSO solution, in ppm downfield from TMS.A, barbituric acid'"; B, 5-monosubstituted barbiturates"'; C, 5,5disubstituted barbiturates with equivalent C-4 and C-6 carbonyl group^^^.'^^""^'.'^^. D, 541'-methylbutyl)-or (a-methylbenzyl)-Ssubstitutedb a r b i t ~ r a t f f ~ ~ . E, ' ~ Na ~ . 'salts ~ ~ ; of 5,5disubstituted barbiturates recorded in D,O solution, DSS as an internal standard'20.'26; F, l-methyl-5,5disubstituted barbiturate^'^^^'^'; G, 1,3dimethylbarbituric acid'2s; H, 1.3dimethylK,1,3dimethyl-5-arylidenebarbit~rates.'~~ 5,5diethylbarbituricacid75;I, 5,Sdisubstituted 2-thiobarbiturates'l9.lz4; J, 5-arylidenebarbit~rates'~~; 9

246

JACEK T. BOJARSKI

et

al.

[Sec. 1I.B

the C-4 and C-6 carbonyl groups but is not observed at the C-2 carbonyl group, as evidenced by changes in chemical shifts. The exocyclic C=C bond is strongly polarized with an electron deficiency at C-7. The substitution of an electron-donating substituent R in 19 by an electron-attracting one results in an upfield shift of the C-7 atom by 4.5 ppm and in a longer downfield shift of the C-5 atom by 13 ppm.'283*29 The chemical shifts of the NMe carbon atoms are almost independent of substituents at C-5. The C-4 and C-6 atoms can show separate resonances as a result of a chiral center in the side chain for compounds 18(R3 = R4 = H or Me),75*'203124*126 E,Z isomerism around the exocyclic C=C bond for ylidene derivatives (19),128*'29 or for N-monomethylated barbiturates(18)(R3= H, R4 = Me)'25 (Fig. 3). Differences in the chemical shifts of the C-4 and C-6 carbonyl groups for 18(R1 = 1'-methylbutylor 1'-phenylethyl, R3 = R4 = H)are0.1-1.1 ppm and the degree of nonequivalence depends on the R2 substituent, while 5ethyl-5-isopropylbarbituric acid, without a center of chirality, shows only one signal for these carbon atoms. However, two C-4- and C-6-atom signals of N methylbarbiturates (18) are differentiated by 0.5-1.5 ppm.Iz4 The nonequivalence of the C-4 and C-6 atoms in 5-arylidenebarbiturates (19) is dependent on the nature of the R substituent, and for p-NO, and p-NMe, groups equals 1.4 and 2.0 ppm, respectively. The NMe carbon atoms (C-8, C-9) of 1,3-dimethyl-5-arylidenebarbiturates (19) are also nonequivalent, and the differences in their chemical shifts amount to 0.6-0.8 ppm.Iz8 According to Haslinger and WolschannIz8 the C-6 atom in 5-arylidenebarbiturates (19)is more shielded than C-4 because of the steric interaction of the carbonyl oxygen with the aromatic ring, but Craik et al., introducing the idea of the MLF (molecular lines of forces),suggest interactions through bonds.130 Okada and Esaki carried out a detailed analysis of the 13C-NMR chemical shifts of all sp3 carbon atoms for 5-mOnO- and 5,5-dialkylbarbiturates and calculated equations based on additivity for chemical shifts of these atoms at position 5 and in the side chain.'2'*122

-

5. Mass Spectrometry 38 Electron-impact (El) mass spectra of numerous barbiturates' 0 8 * ' reflect the high stability of the barbituric acid ring. According to Costopanagiotis and Budzikie~icz,'~'unsubstituted barbituric acid $as the molecular ion m/z 128. The base peak corresponds to CH,=C=Oand a cleavage of the ring occurs by the elimination of the CO and HNCO molecules. The formation of O=C-CH,-C=O+ also is observed, and loss of a hydrogen atom yields O=C=CH-C=O+. However, barbiturates

Sec. II.B]

BARBITURIC ACID

247

containing alkyl or alkenyl substituents at the C-5 position do not show observable molecular ions (20). Owing to an easy initial fragmentation, there are three types: (i) elimination of an olefin from the molecular ion via McLafferty rearrangement for compounds where ethyl or longer substituents are present, (ii) elimination of the 5-substituent as a radical, and (iii) elimination of an HX molecule or X radical for barbiturates substituted in the side chain. Because of these three processes, intense ions 21-23 are observed (Scheme 2). The elimination of HNCO from the molecular ion does not 26-29 are formed from 21-23 by a further cleavage of C0 c c ~ r .Fragments I~~ 5 substituents. The elimination of HNCO from a barbituric acid ring produces

H I

(211

-x. l

-

c

E. Haslinger and P. Wolschann, Bull. Soc. Chim. Belg. 86,907(1977). C. N. Robinson and C. C. Irving, J . Heterocycl. Chem. 16,921 (1979). I 3 O D.J. Craik, R. T. C. Brownlee, and M. Sadek, J. Org. Chem. 47,657(1982). 1 3 1 A. Costopanagiotis and H. Budzikiewicz, Monatsh. Chem. 96,1800(1965). H. F. Gruetzmacher and W. Arnold, Tetrahedron Lett., 1365 (1966). 1 3 3 R. T. Coutts and R. Locock, J. Pharm. Sci. 57,2096(1968). 134 R. T. Coutts and R. Locock, J . Pharm. Sci. 58,775(1969) J. N. T. Gilbert, B. J. Millard, and J. W.Powell, J . Pharm. Pharmacol. 22,897(1970). M. Mizugaki, Y. Suzuki, M. Uchiyama, and H. Abe, Eisei Kagaku 17, 241 (1971)[CA 76. 68,814(1972)l. 13' M. Klein, Recent Den Mass Spectrom. Biochem. Med. 1,471 (1978). S. Dilli and D. N. Pillai, Aust. J . Chem. 29,1769 (1976).

248

[Sec. 1I.B

JACEK T. BOJARSKI et al.

ions 30 and 32-35. Fragmentation patterns presented in Scheme 2 were confirmed by accurate mass measurements and metastable ions.' 37 Fragl mentation of 24 to open-chain ion 31 is also postulated.'08

21

IX-OH1

1' HOCH~CHI H*N-"

0

24

-

(30)m/r 129

~,-C=C=O

I

CONW (31) m b ff2 WO*

(32)mlr f12

(SSI nb f24

Watson and Falkner' 3 9 ~ 1 4 0investigated ELMS of 1,3-bis(trimethylsilyl)5,5-disubstituted barbiturates (36).They found that these compounds have a molecular ion and give the characteristic fragment M - 15 (37) formed by the elimination of a CH, radical from one of the trimethylsilyl moieties. This fragmentation pattern was confirmed by the observation that trimethyl-dgsilyl derivative 36 loses only 18 (not 15) mass units from the molecular ion.

140

J. T. Watson and F. C. Falkner, Org. Mass Spectrom. 7,1227 (1973). F. C. Falkner and J. T. Watson, Org. Mass Spectrom. 8,257 (1974).

Sec. II.B]

BARBITURIC ACID

249

A strong interaction of the aromatic substituent with the pyrimidine ring in 5-arylidenebarbituric acid derivatives (38)results in the stabilization of the whole molecule. This stabilization is reflected in their EI mass spectra. In most cases this shows the molecular ion M' or quasi-molecular ions [M - HI' or [M - R]', where R is a substituent on the aromatic Klein13' suggests further ring fragmentation by the elimination of HNCO and CO molecules and proposes, for 5-benzylidenebarbituric acid, the mechanism shown in Scheme 3. However, Ramana and Vi~wanadharn'~'claim that the

lldz 216 190%)

I

\

SCHEME 3

molecular ion 38 loses H,NCONHCO or H - radicals to form fragments 39 and a cyclic cation 40,respectively (Scheme 4). The H atom is eliminated from the aromatic ring during cyclization.This was confirmed by the mass spectrum D. V. Ramana and S. K. Viswanadham, Bull. Chem. SOC.J p n 53,3004(1980).

250

JACEK T.BOJARSKI et al

[Sec. 1I.B

SCHEME 4

of 5-benzylidenebarbituric acid perdeuterated in the aromatic ring. This compound gives [M - D]' ion, and the formation of [M - HI' ion was not observed. Additional evidence for the formation of 40 is the fragmentation of 5-arylidene derivatives substituted in the aromatic ring. The ortho-substituted derivative 38 shows the presence of [M - R] ion, but for meta- and parasubstituted compounds this ion was not observed. Thus the fragmentation pattern of 5-arylidenebarbiturates proposed by Ramana and Viswanadham seems to be more feasible. EI mass spectroscopy gives valuable information about the fragmentation of barbiturates, but the molecular ion is not usually observed. The presence of the molecular ion is very important for the identification of particular derivatives. Therefore, other methods of ionization of a molecule are also employed. In field desorption (FD) and positive-ion chemical ionization (PICI) mass spectrometry of barbiturates, the molecular ion M' and/or quasimolecular ' ~ ~ et show that the ion [M + 13' (41) are always ~ b s e r v e d . ' ~ * -Fales +

H

14*

M. M. Fales, G.W.A. Milne, and T.Axenrod, Anal. Chem. 42, 1432 (1970).

Sec. II.B]

BARBITURIC ACID

25 1

PIC1 MS of barbiturates substituted at the C-5 position by alkyl, alkenyl, or aromatic substituents give [M + I]' (41) ion, which is the base peak. Barbiturates containing only aliphatic substituents at that position give in their FD MS the [M + I]' ion that is 2-6 times more intense in relation to the molecular ion M'. Elongation of the carbon chain at that position results in an increase of the relative abundance of the [M + I]' ion. On the other hand, a cyclic substituent at the 5-position causes a decrease of the relative intensity of the [M + 13' ion, and molecular ion M + is the base ~ e a k . ' ~ ~ . ' ~ ~ The negative ion chemical ionization' (NICI) of some barbiturates is also d e ~ c r i b e d . ' ~ ~ -The ' ~ * molecular ion M7 (42) is formed by electron capture, and this is followed by the elimination of the H atom or R radical, yielding stable anions 43-45 (Scheme 5). Anion 46, present in low abupdance, may arise from a McLafferty rearrangement. Ring cleavage is manifested by the presence

OToH N

R

R'

SCHEME5 D. E. Games, A. H. Jackson, K. T. Taylor, and N. J. Haskins, Adu. Mass Spectrom. Biochem. Med. 1,383 (1976). 144 H.-R Schulten and D. Kiimmler, Anal. Chim. Acta 113,253(1980). 14' D. F.Hunt, G . C. Stafford, F. W. Crow, and J. W. Russell, Anal. Chem. 48,2098(1976). 146 I. Dziddc, D. 1. Carroll, R. N. Stillwell, M. G . Hornig, and E. C. Hornig, Adu. Mass Spectrom. A7,359 (1978). 14' D. Frangi-Schnyder and H. Branderberger, Fresenius'Z. Anal. Chem. 290,153(1978). '41 L.V.Jones and M. J. Whitehouse, Biomed. Mass Spectrom. 8,231 (1981). 143

252

[Sec. 1I.C

JACEK T. BOJARSKI et al.

of the NCO- ion ( m / z42), which usually has a low relative intensity. The base peak in the NICI is dependent on the nature of the R and R' substituents. Thus all 5-ethylbarbiturates (R = Et) yield the base peak [M - R']- 45, while 5allylbarbiturates (R = allyl) give [M - R]- 43 as the base peak.

C. STRUCTURE AND CONFORMATION 1. Structure and Conformation in the Solid State

a. Hydrogen Bonding and Polymorphism. In the crystalline state the trioxo structure is typical for barbituric acid and its derivatives (cf. Section 11,A). Crystallographic data show that barbiturates generally have lowsymmetric crystal systems, i.e., monoclinic or sometimes triclinic (Table V). In the isolated molecule of barbituric acid and its 5-mOnO-, 5,5-di-, and 1,3,5,5-tetrasubstitutedderivatives,all with the same 1,3-substituents,a flat or almost flat pyrimidine ring is symmetric about the C, line (C-5 C-2)'49*'50 (Fig.4). CNDO/2 and PCILO calculations show that for the isolated molecule of 5,5-diethylbarbituric acid a distribution of atomic charges is symmetric about that C, line.60-'5' - a *

TABLE V CRYSTAL STRUCTURES OF SELECTED BARB~TURATES

Substituents (trivial name)

Crystal system'

5-Ethyl 5,S-Diethyl (Barbital I) 5.5-Diethyl (Barbital 11) 5.5-Diethyl-1-methyl(Metharbital) S-Ethyl-5-(3',3'-dimethylbutyl) (y-Methylarnobarbital) trans-5-But-1'-enyl-5-ethyl 5,5-Diallyl (Dial) 5,5-Diallyl-l-cyclohexyl

M TG M M M

T M M

Zb

H-Bond mode'

4

References 152 16

18 4 4 4

16

154 155

2 8

d d

4

C

156 157 158

' M, monoclinic; T, triclinic; TG, trigonal.

* Number of molecules per cell.

' H-Bond modes shown in Fig. 5.

149

B. M. Craven, C. Cusatis, G. L. Gartland, and E. A. Viuini, J . Mol. Struct. 16,331 (1973). L. Dupont, D. Dideberg, and D. Pyzalska, Acta Crystallogr., Sect. B B30,2447 (1974). D. Voet, J. Am. Chem. Soc. 94,8213 (1972).

Sec. II.C]

BARBITURIC ACID

253

H .. -0.33

I

'H

0

0

-0.34

FIG.4. Distribution of atomic charges in the 5,5-diethylbarbituricacid molecule by CNDO/2 method.151

In the crystalline state, barbiturates show several modes of intermolecular hydrogen bonding, which differ by the number of hydrogen bonds formed between the NH and CO groups (Fig. 5 ) (Table V). For various hydrogenbonding modes (Fig. 5 ) small differences in bond lengths, bond angles, and atomic charges are ob~erved.'~.' 7*149*152-'59 These hydrogen bonds are responsible for layer packing in the crystal lattice. Weak intermolecular van der Waals interactions of carbonyl groups are also responsible for the threedimensional packing of the molecules in the crystal structure.' 7 ~"*' 1 54*160 Three modes of these van der Waals interactions are shown in Fig. 6, and it is noteworthy that the distance between the C-2 carbonyl groups, for example, in 5,5-diethyl- 1-methylbarbituric acid (Fig. 6, interaction type A) is 3.075 A, which is close to the sum of the calculated van der Waals radii of 3.1 Both hydrogen bonding and intermolecular van der Waals interactions are responsible for the polymorphism of barbiturates. The stability of different polymorphic forms is responsible for their biological availa7*88*149~161-167 Some barbiturates have many polymorphic forms; bilit~.'~.' B. M. Gatehouse and B. M. Craven, Acta Crystallogr., Sect. B B27, 1337 (1971). B. M. Craven and E. A. Vizzini, Acta Crystallogr., Sect. B B27, 1917 (1971). 154 H. Wunderlich, Acta Crystallogr., Sect. B B29, 168 (1973). G. L. Gartland and B. M. Craven, Acta Crystallogr., Sect. B B27, 1909 (1971). G . P. Jones and P. R. Andrews, J. Cryst. Mol. Struct. 11, 125 (1981). 15' C. Escobar, Acta Crystallogr., Sect. B B31, 1059 (1975). D. Dideberg, L. Dupont, and D. Pyzalska, Acta Crystallogr,, Sect. B B31.685 (1975). J. R. Ruble, A. C. Wang, and B. M. Craven, J. Mol. Struct. 51,229 (1979). I6O R. Anulewicz, Pol. J . Chem. 55, 187 (1981). 161 B. M. Craven and E. A. Vizzini, Acta Crystallogr., Sect. B B25, 1993 (1969). P. P. Williams, Acta Crystallogr., Sect. B B29, 1572 (1973). H. M. El-Banna, A. R. Ebian, and A. A. Ismail, Pharmarie 30,455 (1975). 164 R. Kaliszan and J. Halkiewicz, Pol. J. Pharmacol. Pharm. 27,579 (1975). I. Grabowska and R. Kaliszan, Pol. J . Pharmacol. Pharm. 28,529 (1976). 166 J. Caillet and P. Claverie, Acta Crystallogr., Sect. B B36, 2642 (1980). B. M. Craven, R. C. Fox, and H.-P. Weber, Acta Crystallogr., Sect. B B38, 1942 (1982). 152

254

JACEK T. BOJARSKI

[Sec. 1I.C

et a/.

--+--q-.

.

I

\ c=o /i

I

i

:

I

i/

O=C :

i/

:

\; ,;=a

i\

O=c\

(A)

(6)

(C)

FIG.6. Three types of van der Waals interactions in barbiturates.

for example, 6 forms for 5,5-diethylbarbituric acid and 13 forms for 5-ethyl-5phenylbarbituric acid have been r e p ~ r t e d . ' ~ . 'The ~ ~ *most ' ~ ~detailed studies on the polymorphism and the relation between the stability of particular forms and their physicochemical properties were carried out for 5 3 diethylbarbituric acid.' 6.88*96s164-'"

Sec. II.C]

255

BARBITURIC ACID

b. Ring Conformations. The 2,4,6-pyrimidinetrione ring of barbituric acid derivatives have planar or nearly planar conformations, but the kind and size of the substituents, as well as their positions in the ring, have significant influence on a deviation of atoms from the ring plane. Two types of conformations of the ring (flat and puckered) are observed. While the flat conformation is observed only in a few cases, i.e., 5,5-diethyl-l-methyl-,' 54 $5diallyl- 1,3-dicyclohexyl-,' " 54 l'-cycloheptenyl)-5-ethyl-,' or trans-5-et hyl54 1 ',3'-dimethylbut- 1'-eny1)barbituric acid,' 7 2 nonplanar conformations are typical for other barbiturates. According to Craven et al., there are two types of puckered conformations of the barbituric acid ring.'49 In the symmetric puckered conformation, the C-2 and C-5 atoms lie on the C2line (Fig. 7). This conformation is observed for a few barbiturate^.^^^'^^^'^^ The asymmetric puckered conformation has the C-5 atom displaced from the best least squares plane of the other ring atoms (Fig. 7). This usually slight deviation of the C-5 atom varies from one barbiturate to another. 4 9 ~ 1 2* ' 4 For example, dihedral angles between the C-4-6-5-C-6 plane and the best least squares plane for 5 4 l'-cycloheptenyl)-5-ethyl-, 5,5-diallyl-, and 5-cyclohexenyl-1,5dimethylbarbituric acid are 3, 10.4, and 29", respectively.' 5 7 Deviations from the planarity of the barbituric acid ring were also predicted by MIND0/3 calculations.'

''

' ' '''J " J

"9'

'' ''

c. Orientation of Substituents. X-Ray crystallographic study shows that 5,5-diethylbarbituric acid has ethyl groups directed above the ring

(a)

(bl

FIG.7. (a) The asymmetric puckered, and (b) the symmetric puckered conformations of the barbituric acid ring.

K. Hollenbach, K. Pintye-Hodi, and G . Kedvessy, Pharmazie 34, 164 (1979). K. Pintye-H6di and K. Hollenbach, Pharmazie 34,807 (1979). K. Hollenbach, K. Pintye-Hodi, and G. Kedvessy, Pharmazie 35.32 (1980). l'' K. Hollenbach, K. Pintye-Hodi, and G . Kedvessy, Pharmazie 35.95 (1980). P.R. Andrews and G . P. Jones, J. Cryst. Mol. Struct. 11, 135 (1981). P. H. Smit and J. A. Kantars, Acta Crystallogr., Sect. B B30,784 (1974). 174 G.P. Jones and P. R. Andrews, J. Cryst. Mol. Struct. 11, 145 (1981). P. R. Andrews and G . P. Jones, Eur. J . Med. Chem.-Chim. Ther. 16,139 (1981). 16'

256

JACEK T. BOJARSKI et al.

[Sec. 1I.C

FIG.8. Orientation of C-5 substituents in barbituric acid derivatives. The heavy line represents the plane of the barbituric acid ring.

system16 in a plane perpendicular to the barbiturate ring (Fig. 8a), and the preferred conformation calculated by PCILO or EHT methods agrees 73*' 74~177and theoretical calentirely.60*'76 Both X-ray data' 7 * 155~' 56*162*1 culations60*'7 5 ~ 1 7 8indicate that the "over-ring" orientation of the 5-ethyl group, as shown in Fig. 5, is favored independently of the nature of the second substituent at this position. For 5-alkyl substituents longer than ethyl, the extended conformation (Fig. 8b)is preferred.60.'55*'75-'78 However, introduction of amethyl group at the ct position results in a predominance of the conformation shown in Fig. 8c, where the methyl group is situated above the barbiturate ring.'73,'75.178 176

I"

B. Laprade, H. Petersen, J. G. Turcotte, and A. N. Paruta, Can. J . Pharm. Sci. 11,54 (1976). P. R. Andrews and G. P. Jones, J . Cryst. Mol. Struct. 11, 125 (1981). G. P. Jones and P. R. Andrews, J . Med. Chem. 23,444(1980).

Sec. II.C]

257

BARBITURIC ACID

Preferred conformations of but- 1'-enyl and but-2'-enyl derivatives are shown in Fig. 8d-f. The double bond of the but-1'-enyl substituent is directed above the ring and partially eclipses the C-4-C-5 ring bond, and the terminal methyl group is folded back at the end of the chain (Fig. 8d).'56"75J78 The double bond of both the cyclohexene ring in 5-(1'-cyclohexenyl)-1,5dimethylbarbituric acid and the phenyl ring in 5-ethyl-5-phenylbarbituricacid are also partially eclipsed by the C-4-C-5 pyrimidine bond.60*'6 2 , 1 79*.180 Similar orientations of substituents with a characteristic S-shape (Fig. 8g) were observed for 5,5-diallylbarbituric acid.' 5 7 Introduction of a methyl group at the tl position with a but-1'-enyl substituent results in a similar favored conformation as in the saturated analogues (Fig. 8c). The over-ring conformation of the but-2'-enyl substituent (Fig. 8f) is also the most stable one.17.174.175.177,178

In compound 47 the aromatic ring and the imide bond are coplanar but orthogonal to the ylidenebarbituric acid moiety.'"

2. Conformation in Solution Quantum mechanical calculations by MIND0/3 suggest that barbiturates with alkyl and/or alkenyl substituents at the 5-position show in solution the same favored conformations as in the solid state'09*'82*'83(Fig. 8). This conclusion is also confirmed by the results of conformational analyses using 'H-and 13C-NMR s p e c t r o s ~ o p y . ' ~ ' *Moreover, '~~ Andrews et al. conclude that these preferred conformations in solution are independent of the ionization state of the barbiturate ring."' Haslinger et al. give an interesting example of weak intramolecular interaction occurring in barbiturates as evidenced by UV-VIS and H-NMR

'

'" P. R. Andrews and J. A. Defina, Int. J. Quantum Chem., Quantum Eiol. Symp. 7,297 (1980). la'

H.-D. Holtje, Arch. Pharm. (Weinheim, Ger.) 310,650 (1977). M. C. Apreda, F. H. Cano, C. Foces-Foces, and S.Garcia-Blanco, Acta Crystallogr., Sect. E B37,1935 (1981). G. D. Daves, R. B. Belshee, W. R. Anderson, and H. Downes, Mol. Pharmacol. 11,470(1975). P. R. Andrews and G. P. Jones, Int. J. Quantum Chem., Quantum Biol. Symp. 6,439 (1979).

258

JACEK T. BOJARSKI el al.

[Sec. 1I.C

FIG.9. Conformation of 5-arylidenebarbituric acid molecule; 0, dihedral angle between the phenyl and pyrimidine rings.

spectroscopy. They show that the phenyl ring in 5-(3'-pheny1propyl)barbituric acid (48) lies above the barbituric acid ring and the strength of the interaction between these rings is significantly dependent on the nature of the substituent R.lE4

(48)

It was also found by 'H-NMR spectroscopy that the phenyl ring in arylidenebarbiturates (5) is twisted in relation to the plane of the ylidenebarbit ~ r a t e . " ~ . ' A detailed analysis of chemical shifts of particular aromatic protons and their coupling constants with the vinyl proton leads to the conclusion that the value of the dihedral angle O(Fig. 9) depends on the nature and position of substitution in the aromatic ring. Ortho substitution in the phenyl ring, where steric effects predominate, results in hindrance to rotation. Thus of the two possible conformations conformer A (Fig. 10) is favored. Moreover, for o-nitro substituted derivative 5 the dihedral angle is 4 3 O . l '

FIG. 10. Two conformations of 5-arylidenebarbiturateso-substituted in the phenyl ring (only arylidene moiety shown). E. Haslinger, H. Kalchhauser, and P. Wolschann, Monatsh. Chem. 113,633 (1982).

Sec. ILD]

259

BARBITURICACID

Rotational barriers about the =C-N and - C = N bonds in 49 and 50 were also investigated; the enamine bonds have AGt values higher by 1520 kJ/mol than the hydrazone bonds.IE5

D. OPTICAL ISOMERS Two types of optically active barbiturates attract the attention of chemists and pharmacologists. In the first, the center of chirality is outside the ring in one of the substituents at C-5 (e.g.,51), in the second, the chirality is associated with the dissymetry of the ring (e.g., 52). Separation of racemic mixtures of

(51)

(52)

compounds of both types were reported by Knabe et ul.186-'89 The enantiomers were obtained by fractional crystallization of salts prepared from barbituric acids and N-methylquininium hydroxide. This procedure has also been used by ~ t h e r ~ ~but~sometimes . ~ ~ was * ~considered ~ ~ - unattractive ~ ~ ~ because of poor yields and low optical p ~ r i t y . ' ~ ~ ' ~ ~ Bobranski et al. reported the resolution of optical isomers of 5-allyl-5-(2'hydroxypropy1)barbituric acid by the fractional crystallization of their Is' 18'

Is8

U. Kolle, B. Kolb, and A. Mannschrenk, Chem. Ber. 113,2545 (1980). J. Knabe and R. Krauter, Arch. Pharm. (Weinheim, Ger.) 298, 1 (1965). J. Knabe, R. Krauter, and K. Philipson, Tetrahedron Lett., 571 (1965). J. Knabe and K. Philipson, Arch. Pharm. (Weinheim, Ger.)299,231 (1965). J. Knabe, D. Straws, and C. Urbahn, Pharmazie 23,522 (1968). R. S. Perry, H. Downes, and R. Karler, Fed. Proc., Fed. Am. Soc. Exp. Biol. 28,776 (1969). H. Downes, R. S. Perry, R. E. Ostlund, and R. Karler, J . Pharmacol. Exp. Ther. 175,692(1970). E. Gordis, Biochem. Pharmacol. 20,246 (1971). K. Miyano and S. Toki, Drug Metab. Dispos. 8, 111 (1980). K. Miyano, T. Ota, and S. Toki, Drug Metab. Dispos. 9,60 (1981). P. R. Andrews, G. P. Jones, and D. B. Poulton, Eur. J. Pharmacol. 79,61 (1982).

260

[Sec. 1I.D

JACEK T. BOJARSKI et a/.

hydrophthalate ester salts with quinine and subsequent acid hydrolysis of diastereomeric salts and enantiomeric esters.' 96 Camphorosulfonic acid was used for the formation of diastereomericsalts of chiral 1-methyl-,1-ethyl-,and 1-cyclohexylbarbiturateswith piperidine, pyrrolidine, and dimethylamine as basic substituents bound through their N atoms with the C-5 atom of the barbituric ring. Separation and hydrolysis of these salts yielded appropriate enantiomers with optical purity better than 95%.'97-'98 Blaschke described satisfactoryseparation of enantiomers of 52 and several l-methyl-5,-5-disubstitutedbarbiturates by column chromatography on microcrystalline cellulose triacetate, but for some pairs of C-5 substituents (phenyl, propyl and 1-cyclopentenyl, ethyl) only partial separation was achieved, while for ethyl, propyl and 2'-pentyl, vinyl pairs no separation was observed.' Synthetic approaches to optically pure enantiomers of barbiturates followed general methods of preparation of these compounds, but pure enantiomers of known configuration have been used as the substrates. Thus, R(-) and S( +) enantiomers of 51 and closely related compounds (54) were prepared from the enantiomers of 3-methylhexanoic acid (53) by the reaction sequence shown in Scheme 6.73*200

COOH I CH, 1 'CH-CH, I (CHZ)~

COOR

I

I

*CH-CH)

(CooEt)2 c

I

[CHI),

I

I

CHI

H-UCOOEt).

CHa EtOH

c H,

:($ . ,:

CH,(53)(CHA-CH

I

+CH-CH,

I (CHtl, I CH,

cx(NH,\,<

1-H.

R- CLCOOEt),

I

(54)

*CH-CH,

I I

(CH,), CH,

(Ma) R = Et, X = 0

(54b) R

= Et, X = S (544 R = H , X = 0 ( 5 4 ) R = allyl, X = 0 (54e) R = allyl, X = S

SCHEME 6

Sec. II.D]

BARBITURIC ACID

26 1

A similar procedure was used for preparation of enantiomers of 5-allyl-5(l'-methy1-2'-pentynyl)-Zthiobarbituricacid201 and 5-(1',3'-dimethylbutyl)Sethylbarbituric acid.202 Knabe et u1.203-208prepared 52 and a series of 5,5-disubstituted analogs (59) starting from the enantiomers of substituted cyanoacetic acids (55) previously separated via their salts with (lR,2R)-Zarnino-l-phenylpropane1,3-diol (Scheme 7). An interesting feature of this procedure is that starting from the same enantiomer of 55 both (+)and (-) forms of 59 can be obtained

X

n + NYCNH-k (57)

-

H' NH

SCHEME 7

B. Bobranski, M. Wilimowski,J. Barczynska, R. Seniuta, B. Sdzimirska, and M. Witkowska, Arch. Immunol. Ther. Exp. 21,299 (1973). 19' J. Knabe and J. Reinhardt, Arch. Pharm. (Weinheim, Ger.) 315,706 (1982). 198 J. Knabe and J. Reinhardt, Arch. Pharm. (Weinheim, Ger.) 315,772 (1982). 199 G. Blaschke, Angew. Chem., Int. Ed. Engl. 19, 13 (1980). ' O 0 C. E. Cook and C. R. Talent, J. Heterocycl. Chem. 6,203 (1969). *01 F.I. Carroll, A. Philip, D. M. Naylor, H. D. Christensen, and W. C. Goad, J. Med. Chem. 24, 196

1241 (1981).

K. C. Rice, J . Org. Chem. 47,3617 (1982). 203 J. Knabe and J. Straws, Angew. Chem.,Int. Ed. Engl. 7,463 (1972). '04 J. Knabe and H. Junginger, Pharmazie 27,443 (1972). 205 J. Knabe and N. Franz, Arch. Pharm. (Weinheim, Ger.) 308,313 (1975). ' 0 6 J. Knabe and N. Franz, Arch. Pharm. (Weinheim, Ger.) 309,173 (1976). 'O'J. Knabe, H. P. Buch, V. Gradmann, and I. Wolff, Arch. Pharm. (Weinheim, Ger.) 310,421 202

(1977). 'On

J. Knabe and W. Furst, Arch. Pharm. (Weinheim, Ger.) 312,86 (1979).

262

[Sec. 1I.D

JACEK T. BOJARSKI et al.

separately, depending on the alternative routes of synthesis. The scope and details of this method are discussed in a review published in 1978.’09 The synthesis of l-methyl-5-phenyl-5-propyl-2-thiobarbituric acid by the condensation of appropriate 56 with 57 proved unsuccessful but has been accomplished by a direct reaction of phenylpropylcyanoacetic acid with 57 in the presence of dicyclohexylcarbodiimide and hydrolysis of the resultant 4imino-2-thiobarbiturates (58).’ l o Several barbiturates (e.g. 60-62) having two chiral centers exist in both enantiomeric and diastereomeric forms. The stereoisomers of 60 were obtained by Doran” and exhibited different pharmacological activity.”’ Four possible optical isomers of 61 were obtained by Miyano and Toki by enzymatic and chemical methods.193 Separations of diastereomeric mixtures were achieved by TLC and column chromatography on silica gel. The use of an adsorption of glucuronides of 61 on XAD-2 resin was advantageous for preliminary isolation of these compounds from urine. 94

CHpCH-C

*

C&Is--C‘C-CH

go:*q,i 7

Ma

tle

%I

“H

\

LH3

x

in3

CH~-*CH-M~-CH !ti

OH

(60)

(61)

(62)

Carroll and Morelandzi3 synthesized all stereoisomers of 62 (R = Et or allyl) and their 2-thio analogs from optical isomers of 3,5-dimethylvalerolactone by the method analogous to that in Scheme 7 and assigned absolute configurations. This permitted comparisons with appropriate metabolites isolated from in uioo studies. Two diastereoisomers of 62(R = Et) [3’ (R), l’(R) and 3’(R), l’(S)] have been found in the urine of dogs after administration of the R( +) enantiomer of 51.’14 Optical purity of barbituric acid enantiomers was determined by the isotope dilution method using 2-14C-labeled compounds ’15 or by an NMR 209

210

zll ’12

J. Knabe, W. Rummel, H. P. Buch, and N. Franz, Arzneim. Forsch. 28, 1048 (1978). J. Knabe and L. Schambet, Arch. Pharm. (Weinheim, Ger.) 315,878 (1982). W. J. Doran, J. Org. Chem. 25, 1737 (1960). W. R. Gibson, W. J. Doran, W. C. Wood, and E. C. Swanson, J . Pharmacol. E x p . Ther. 125,23 (1959).

F. I. Carroll and G . N. Moreland, J . Med. Chem. 18,37 (1975). K. H. Palmer, M. S. Fowler, M. E. Wall, L. S. Rhodes, W. J. Waddell, and B. Baggett, J . Pharmacol. E x p . Ther. 170,355 (1969). 2 1 s J. Knabe and V. Gradmann, Arch. Pharm. (Weinheim, Ger.) 306,306 (1973). 213

Sec. III.A]

BARBITURIC ACID

263

method using lanthanide shift reagent^.'^^.^''*^'^ The optical rotations of pure optical isomers allowed estimations of optical purity of partly resolved enantiomers reported earlier.”’ The assignments of absolute configurations to optical isomers of barbiturates were made on the basis of correlations with compounds of known configuration after appropriate chemical conversions, ORD, CD and NMR spectra, and X-ray analysis.’93~’98*209.2”7 Many workers report different stereospecificpharmacological effectiveness, metabolism, or pharmacokinetic parameters for the stereoisomers of barbiturates investigated both in uitro and in uiuo.209~218-228 The results of these studies significantly contribute to a better understanding of the mechanisms of action of barbiturate drugs at the molecular level and make questionable Doran’s statement that “whereas structural isomerism has a significant bearing on pharmacological activity in the barbituric acid series, stereoisomerism is apparently of lesser irnportan~e.”~

111. Reactivity of Barbiturates

A.

REACTIONS AT THE C-5 ATOM

Barbituric acid has two active hydrogen atoms at the 5-position which can be replaced by various substituents to make the molecule biologically a ~ t i v e . The ~ ~introduction ~ - ~ ~ ~ of simple alkyl substituents into this position

’16 ’17

’I8

’19 ’O

J. Knabe and V. Gradmann, Arch. Pharm. (Weinheim, Ger.)310,468 (1977). J. Knabe and W. Wunn, Arch. Pharm. (Weinheim, Ger.)312,973 (1979). I. K. Ho and R. A. Harris, Annu. Rev. Pharmacol. Toxicol. 21,83 (1981). G . Wahlstrom, Eur. J. Pharmacol. 59,219 (1979). D. A. Mathers and J. L. Barker, Science 209,507 (1980). K. Miyano and S . Toki, Drug Metab. Dispos. 8,104 (1980). F. Leeb-Lundberg, A. Snowman, and R. W. Olsen, Proc. Natl. Acad. Sci. U.S.A. 77, 7468

’” ’’’

( 1980).

M. K. Ticku, Biochem. Pharmacol. 30,1573 (1981). J. R. Holtman and J. A. Richter, Biochem. Pharmacol. 30,2619 (1981). J. Knabe, H. P.Buch, and J. Reinhardt, Arch. Pharm. (Weinheim, Ger.) 315, 832 (1982). 226 J. Baldauf, H. Wilbert, and H. P. Buch, Arzneim.-Forsch. 32, 1281 (1982). P. Skolnick, K. C. Rice, J. C. Barker, and M. S.Paul, Brain Res. 233, 143 (1982). 228 M. Van der Graaff, N. P. Vermeulen, R. P. Joeres, and D. D. Breimer, Drug Metab. Disp. 11, 223 224

’” ’”

489 (1983). 229 ”O

T. Ukita, Y. Kato, M. Hori, and H. Nishizawa, Chem. Pharm. Bull. 8, 1021 (1960). I. Weinryb, I. M. Michel, J. F. Alicino, and S. M. Hess, Arch. Biochem. Biophys. 146, 591 (1971).

’”A. J. Stuper and P. C. Jurs, J. Pharm. Sci.67,745 (1978). 232 233

B. Testa, Pharm. Acta Helo. 53, 143 (1978). R. D. Budd, F. C. Yang, and K. 0.Utley, Clin. Toxicol. 18,317 (1981).

264

[Sec. 1II.A

JACEK T. BOJARSKI et al.

is easy and is similar to that in malonic ester^.^ Complex substituents can be introduced, using indole derivatives. Rao and Chalmers reported that the yields reaction of barbituric acid with 3-isopropylaminoethyl-2-methylindole 5-(2’-isopropy1amino)ethylbarbituric acid in the presence of piperidine2 3 4 [Eq. (l)]. Suvorov et al.235described the C-5 substitution of barbituric and

2-thiobarbituric acids (64; R’ = Bu, Ph; X = 0, S)using 63 (R = H, OCH,) CEq. (211.

Y

The formation of some 5-alkyl or 5-arylmethylbarbituric acids has been studied by Sekiya et u1.236-238The barbituric acid derivatives 65 (0-,m-, psubstituted phenyl, benzyl, styrenyl; R’, RZ = H and/or methyl) containing a methylidene bond at the 5-position can be reduced by triethylammonium formate (TEAF)in high yield [Eq. (3)]. Similarly, 5-arylaminomethylene-and 5-alkylaminomethylene-substitutedbarbituric acids can be converted to 5methylbarbituric acids.238

R. P. Rao and A. H. Chalmers, Indian J . Chem. 6,336 (1968). N. N. Suvorov, V. S. Velezeva, V. V. Vampilova, and J. N. Gordieev, Khim. Geterotsikl. Soedin., 515 (1974). 236 M. Sekiya and C. Yanaihara, Chem. Pharm. Bull. 17,747 (1969). 237 M. Sekiya, C. Yanaihara, and J. Suzuki, Chem. Pharm. Bull. 17,752 (1969). 238 M. Sekiya and C. Yanaihara, Chem. Pharm. Bull. 17,810 (1969). 234

235

Sec. III.A]

BARBITURIC ACID

-

R*

R’-c I

HOQO

TEAF

N ~ s

O e

R’CW,

N\R’

265

(3)

0

O

1651

Ethier and Neville239 presented the facile oxidative methylation of 5- , vanillylidene and 5-benzylidenebarbituric acids in DMF with methyl iodide in the presence of Ag20 leading to 1,3,5,5-tetramethyIbarbituric acid (66). According to the authors, the oxidative cleavage with methylation followed the interaction of silver ion with the olefinic double bond. H

I

zg

NYo+

410

0 NM ,.

CHO

Q

Oh

OM0

16s)

Barbiturates smoothly undergo the Mannich reaction. Although the aminomethyl group is usually introduced in the 1- and/or 3-position of the barbituric ring (see Section III,B), there are known cases of this reaction at the 5-position. Sladowska obtained the series of 1,3-dicyclohexyl-5-alkyl-5aminomethylbarbituric acids (67; R = Et, allyl; R‘ = 1-piperidinyl, l-pyrrolidinyl, 1-morpholinyl) from 1,3-dicyclohexyl-5-alkylbarbituric FHW

OYNYO

167)

Unsubstituted, 1-mono- or 1,3-dialkyl- and/or phenyl-substituted barbituric acids (68)can be converted to 5-formimidoyl derivatives by a reaction with s - t r i a ~ i n e ~[Eq. ~ ’ (4)]. The reaction of orthoformates with CH,-acidic molecules (diethylmalonate, malononitrile, etc.) is used to introduce the formyl (or its tautomer I. C. Ethier and G. A. Neville, Tetrahedron Lett. 52,5297 (1972). H. Sladowska, Farmaco, Ed. Sci. 32,866 (1977). 241 A. Kreutzberger, Arzneim.-Forsch. II 28,1684 (1978). 239 240

266

[Sec. 1II.A

JACEK T. BOJARSKI et al.

R

R

hydroxymethylene group) into the latter compounds. Wolfbeis and J ~ n e k ~ ~ ~ reported a simple two-step synthesis of hydroxymethylene 1,3-dicarbonyls, including barbituric acid derivatives, using orthoesters shown in Eq. (5).

op6

ph

Ph

+

H

NYi

0

I

0

KOH_op

HC(OEt),, H--f PhNH

C

(5)

I

HO

Barbituric acids condense smoothly with aldehydes under moderate conditions, yielding 5-ylidene The presence of low electron density at the C-5 position in the exocyclic C=C bond, owing to conjugation with the carbonyl groups in the 4- and 6-positions, causes the nucleophilic addition reaction in these b,arbiturates. 5-Arylidenebarbituric and thiobarbituric acids react with compounds containing an active methylene group under Michael reaction condit i o n ~ . Compounds ~ ~ ~ * ~ 69 ~ (R ~ = H, p-NO2, p-C1; X = 0, S) have been obtained in the reaction of 5-arylidenebarbituric or thiobarbituric acids with cyclohexanone, benzyl phenyl ketone, camphor, ethyl ester of phenylacetic acid, or nitromethane. The reaction with ethyl cyanoacetate or ethyl 0.S. Wolfbeis and H.Junek, Z. Naturforsch. B: Anorg. Chem., Org. Chem, 34B,283 (1979). W. M. Vviedenskij, Khim. Geterotsikl. Soedin., 1092 (1969). 244 G. Haas, J. L. Stanton, A. Sprecher, and P. Wenk, J . Heterocycl. Chem. 18,607 (1980). 245 U. Elben, H.-B. Fuchs, K. Frensch, and F. Vogtle, Liebigs Ann. Chem. 1102 (1979). 246 M. El-Hashash, M. Mahmoud, and H. El-Fiky, Reo. Roum. Chim. 24, 1191 (1979). 247 A. F. Fahmy, M. M. Mohamed, A. A. Afify, M. Y . El-Kady,and M. A. Ef-Hashash, Rev. Roum. Chim. 25, 125 (1980). 242

243

Sec. III.A]

267

BARBITURIC ACID

(690)

R= 0

(69b)

R= O f H - E Q

9

(701

0

( 6 9 ~ ) R= O F H - t O O l l

acetoacetate yielded 70 (R = H, p-N02, p-C1; X = NH,CO, CH,CO; R’ = NH2, OH). N,N-Disubstituted barbiturates (71; R’ = R 2 = Me; X = 0,S) react with alkyl cyanoacetates or malononitrile in DMF in the presence of KOH to yield crystalline salts (72), which undergo cyclization to 1,2,3,4tetrahydro-7H-pyrano[2,3d] pyrimidines (73), while N,N-unsubstituted anilinomethylenebarbituric acids (71, R’ = R2 = H) under the same conditions yield pyrimidine derivatives (74, R’ = R2 = H).248 5-Ylidenebarbiturates

‘1’

5’ K’

(71)

‘1’

/

(72’

I

H

have also been postulated as intermediates formed during the condensation of barbituric acids (75; R 1 = H, Me, Ph; R 2 = H, Me, Ph, p-N02-C,H4) with 0-,m-,p-Cl-C6H4, p aldehydes (76; R 3 = H, Me, Ph, m-, p-NO&&, MeCOO-C&, m-Me-C,H,, O-HO-C,H,) and p h e n y l a ~ e t y l e n e .The ~~~ H. Wipfler, E. Ziegler, and 0.S. Wolfbeis, 2.Natuforsch., B: Anorg. Chem., Org. Chem, 33B, 1016 (1978). 249 K. E. Schulte, V. Weissenborn, and G. L. Tittel, Chem. Ber. 103,1250 (1970). 248

268

[Sec. 1II.A

JACEK T. BOJARSKI et al.

(75)

(76)

(77)

(78)

condensed pyran systems 78 were formed by the 1,Ccycloaddition of phenylacetylene to the 5-ylidene compounds 77. The stabilized sulfonium ylide 79 was obtained in the reaction of barbituric acid with DMS0250*25' and was the intermediate in the formation of 80 (R = R' = H, Me).252

(79)

180)

There are several examples of the addition of barbituric acid to other

corn pound^.^^ 3--255 Barbituric acid and its 2-thio analogue undergo nucleophilic addition to purine and its 2- and/or 8-substituted derivatives (81; R = H,NH,; R' = H, SO,Me, CF,). The reaction, carried out in water in the presence of K,C03, yields adducts 82 (R = H, NH,; R' = H, SO,Me,

(81)

(82)

CF,; X = 0,S).253As the products of addition of 5-alkyl barbituric acids (83; R = Me, Et, Pr, i-Pr, Bu, t-Bu) to a,&unsaturated ketones (84;R' = p-OMe, p Br, p-CI, p-OH, p-NO,), various 5,5-disubstituted derivatives (85) were formed. 254 The addition of barbituric or 1-substituted barbituric acids (86; 250 251

A. F. Cook and J. G. Moffatt, J . Am. Chem. SOC.90,740 (1968). D. Martin and H. J. Niclas, Chem. Ber. 102,31 (1969).

252

H. Fenner, H. H. Rossler, and R. W. Grauert, Arch. Pharm. (Weinheim, Ger.)314,1015 (1981).

253

W. Pendergost, J.C.S. Perkin I , 2159 (1973).

254

2s5

L. P. Zalukayev and V. L. Trostyanetskaya,Khim. Geterotsikl. Soedin., 836 (1971). D. Prelim, Diss. Pharm. Pharmacol. 18,31(1966).

Sec. III.B]

269

BARBITURIC ACID

R = Me, Ph) to phenyl isocyanate leads to 5-phenylcarbamoyl barbituric acids (87).229Similarly, the 2-thio compounds are formed in the reaction with

isothi~cyanates.~~’ These reactions occur in pyridine or in ethanol-water solutions in the presence of pyridine or N,N-dimethylaniline. Recently the addition of barbituric acid to arylidene malononitrile has been described.256 As a result of the reaction of barbituric acid with 88 (R = p-F-C,H,, p-BrC6H4),condensed pyrano[2,3-d] pyrimidine systems (89)were obtained.

1

-t RCH-C,

/ CN

CN

(88)

-

-

n

-““:v 7

NC’

-

ICHN g---J ‘CH h

0

H‘

o

AT NITROGEN B. SUBSTITUTION

The imide hydrogen atoms in barbituric acids take part in tautomerism (Section I1,A) so that the alkylation of these compounds leads to a mixture of N- and 0-alkyl derivatives. Levina thoroughly discussed the N-alkylati~n.~ The direct alkylation of barbituric acid preferentially occurs at the C-5 atom rather than at the 1- or 3- position. However, 1-methyl-6-methoxyuracil was obtained as the major product of the action of diazomethane on barbituric a ~ i d . ~ ” .Alkylation of 1- or 5-monosubstituted barbiturates ~~’ Yu. A. Sharanin and G. V. Klokol, Khim. Geterotsikl. Soedin., 277 (1983). K. Ito, K.Nishiie, and M. Sekiya, Yakugaku Zasshi 90, 188 (1970). 258 G. A. Neville and H. W. Avdovich, Can. J . Chem. 50,880 (1972).

lS6

*”

270

[Sec. 1II.B

JACEK T. BOJARSKI et al.

was found to yield the products of N- and/or O - a l k y l a t i ~ n . ~On ~ ~the -~~~ other hand, N-methylation predominates in 5,5-disubstituted and 1,5,5During the methylation of $5trisubstituted disubstituted barbituric acids (90; R = Et, Ph; R = Et; R = R' = allyl) with diazoalkanes, N,N-dialkyl derivatives were obtained as the major products. Small amounts of isomeric N,O-dialkyl derivatives (91 and 92) were also

h

OEt

OEt ( 93)

(94)

produced in these reactions. Moreover, ethylation of 90 (R = Et, R' = 3'methylbutyl) gave additionally two 0,O-dialkyl isomers (93 and 94).262Both mono- and disubstituted p-NO,-benzyl derivatives have the structures of Nderivatives (95).2655,5-Disubstituted thiobarbituric acid (96) can be

r

OYNY (99)

(9%) R' = Et, R 2 = Ph, R' = Me (95b)R' = Me, R 2 = 1-cyclohexenyl-1'-, R3 = Me (9%) R' = Et, R2 = Et, R' = H ( 9 s ) R' = Et, R2 = Et, R' = Me (95e) R' = Et, R2 = Et, R' = p-NO,-benzyl

R. M. Thompson, J . Pharm. Sci.65,288 (1976). M. T. Bush and E. Sanders-Bush, Anal. Biochem. 106,351 (1980). S. Dilli and D. N. Pillai, Aust. J . Chem. 28,2265 (1975). D. J. Harvey, J. Nowlin, P. Hickert, C. Butter, 0.Gansow, and M. G. Homing, Biomed. Mass Spectrom. 1,340 (1974). 263 J. A. Vida, Tetrahedron Lett. 37,3921 (1972). 264 J. F. Menez, F. Berthou, D. Picart, L. Bardou, and H. H. Floch, J . Chromatogr. 129,155 (1976); R. D. Budd. Clin. Toxicol, 16, 189 (1980). 2 6 5 J. Bojarski, W. Kahl, and M. Melzacka, Rocz. Chem. 41,2089(1967); J. Bojarski, W.Kahl, and M. Melzacka, Rocz. Chem. 42,41 (1968). 259 260

Sec. III.B]

27 1

BARBITURIC ACID

converted to N,S-bis(methoxymethy1)derivatives [97,Eq. ( 6 ) ] upon reaction with chloromethyl methyl ether. Further oxidation of 97 gave 98 in excellent yield.' 66

(0s 1

(97)

(98)

The hydrogen atom in the NH group can also be substituted by the acyl r e s i d ~ e . ' ~ ~ * ' ~ Reaction ~ - ' ~ ' of benzoyl chloride with 5,Sdiethyl- and 5-ethyl5-phenylbarbituric acids proceeds in two steps. In the first step, benzoyl chloride reacts with N-nonsubstituted barbiturates, yielding N-monosubstituted derivatives ( 9 9 R' = Et, R' = Et, Ph; R3 = PhCO), which then undergo the self-acylation reaction [Eq. ( 7 ) ] . R'

oJ$To-;Qo

R'

R'

0

ti

R'

'H

I

N,RJ

R'

0

+

o ' ;R;

N'H

(7)

0

(w) The N-carboxymethyl derivatives of barbituric acid can be obtained by condensation of barbiturate with appropriate chlor~esters.'~~ Similarly, Nsubstituted barbiturates containing a basic group at the nitrogen atom were formed. Treatment of 5,5-dialkylbarbituric acid with benzylaminoethyl chloride in the presence of sodium ethanolate led to N-(2'-benzylaminoethyl)5,5-diallylbarbituric The direct introduction of a hydroxyl group onto 1- or 3-positions in the barbituric ring system is difficult, and attempts to accomplish it by direct oxidation with hydrogen peroxide, peracetic, trifluoroperacetic, and 266

267

J. A. Vida, Synth. Commun. 3,105 (1973). L. P. Kuliov, G .M. Stepnova, V. G .Stolarshchuk, and 0.N. Neczajeva, Zh. Obshch. Khim. 30, 1385 (1960).

L. P. Kuliov and A. L. Shesterova, Zh. Obshch. Khim. 31,1378 (1961). 269 J. Bojarski and W. Kahl, Rocz. Chem. 41,311 (1967). 270 J. Bojarski, W. Kahl, M. Melzacka, and W. Pasek, Rocz. Chem. 42,337 (1968). '"B. Heublein, G . Heublein, B. Bockel, and H. Schutz, 2. Chem. 21,443 (1981). 2 7 2 H. Sladowska, Farmaco, Ed. Sci. 35,60 (1980). 273 H. Sladowska, Farmaco, Ed. Sci. 31,714 (1976). 274 S. Bogdanova, Rocz. Chem. 47, 115 (1973).

272

JACEK T. BOJARSKI et al.

[Sec. 1II.B

m-chloroperacetic acid were unsuccessful.275Nevertheless, 5,SdisubstitutedN-hydroxy- (100) and N,N’-dihydroxybarbituricacids (101; R = Et, Ph) were obtained indirectly by the oxidation of the appropriate amino derivatives, followed by acid h y d r o l y ~ i s . ~ ~ ~ , ~ ~ ~

(101)

(100)

R’

R2

Me n-Pr Et Et (100~) Et n-Pr Ph (loOa) Et (1OOe) m-Pr n-Pr (100a)

(100b)

The NH groups of barbituric acids easily take part in Mannich rea c t i o n ~ . ~5-Ethylbarbituric ~~*~~* acid yielded N,C-bis(piperidinemethy1)derivative 102 during aminomethylation with formaldehyde and ~ i p e r i d i n e . ~ ~ ’

3

cE:p,; CH-,

I

N-

N

HI

( 1021

The second NH group in 103 (R = Me, Et; R = Ph, cyclohexenyl) did not undergo further aminomethylation. The reaction led only to N-aminomethyl product 104 (R = Me, Et; R = Ph, cyclohexenyl). This was explained by the formation of the lactim form, which renders the other hydrogen inaccessible to a second condensation reaction owing to the stabilization of the lactim moiety by an intermolecular hydrogen bond.25 W. Cowden and N. Jacobsen, Aust. J . Chem. 31,2517 (1978). W. Cowden and N. Jacobsen, Aust. J . Chem. 35,795 (1982). 2 7 7 L. Rylski, L. Senczuk, K. Falandysz, L. Konopka, and D. Zimna, Acta Pol. Pharm. 24, 369 27s

276

( 1967). 278 279

J. A. Vida and M. L. Hooker, J . Med. Chem. 16,602 (1973). H. J. Roth and R. Brandes, Arch. Pharm. (Weinheim, Ger.) 299,612 (1966).

Sec. III.C]

273

BARBITURIC ACID H

(IOS)

(105)

Danielsson and Dolbyz8' showed that aminomethylation in the 1- and 3positions was possible in both 5,Sdiethyl- and 5-ethyl-5-phenylbarbituric acids when formaldehyde and morpholine were used as the reagents. Furthermore, Werner and FritzscheZ8' found that 1-aminomethylated 5 3 disubstituted barbituric acids 105 [R = piperidinyl bis(2-~hloroethyl)amine] have nonchelated NH groups and that a second aminomethylation is possible at the N-3 atom. H

C.

REACTIONS OF CARBONYL GROUPS

The carbonyl group at the 2-position shows a different character from the other carbonyl groups in the barbituric acid ring. The condensation of barbituric acid with hydrazine, phenyl-, 1,l-diphenyl-,and 2,4-dinitrophenylhydrazine led only to derivatives 106 or 107 (R = R' = Ph; R = H, R = Ph, 2,4-di-N0z-C6H4).282

(106)

(107)

The exclusive formation of 0-alkyl derivatives of barbituric acids was seldom observed, because in the course of alkylation a mixture of products is obtained (Section 111,A). Nevertheless, only 0-alkylation was observed in B. Danielsson and J. Dolby, Acta. Phnrm. Suec. 1,91 (1964). W. Werner and H. Fritzsche, Arch. Pharm. (Weinheim, Ger.) 302, 188 (1969). 282 V. M. Vvedenskii and A. J. Zhvalevskaya, Khim. Geterotsikl. Soedin., 95 (1970). 281

274

[Sec. 1II.C

JACEK T. BOJARSKI et al.

the intramolecular cyclization of 5-halogenoalkyl or N-halogenoalkyl barbituric and thiobarbituric (Section 111,F).Moreover, products 108 (R = H, Ph) of 0-alkylation have been obtained during the action of methanol and HCI on barbituric and N-phenylbarbituric acids."' R

( 108

During treatment with LiAlH4, 5-substituted barbituric acids formed 2oxohexahydropyrimidine derivatives.288 N-Methylated barbiturates (109; R = Ph, 1-cyclohexenyl; R' = Me, Et) were reduced with LiAIH4, giving 110, while such reduction in the presence of AICI, led to l l l . 2 8 9 It was sug-

(no)

(low

(111)

gested that barbiturates would not be reduced with borohydrides unless they had a phenyl ring as one of the 5 - ~ u b s t i t u e n t s . Sodium ~ ~ ~ * ~borohydride ~~ was also considered to be too mild a reducing agent for barbiturates. Nevertheless, 5-ethyl-5-phenylbarbituric acid was found to react with sodium borohydride in aqueous and organic media.292*293 Moreover, 1,3-dimethyl5,Sdibenzylbarbituric acid was reduced when the reaction was carried out in methanol at room temperature for 1 hr.294 Reduction of barbiturates with sodium borohydride in various solvents was investigated in detail by E. E. Smissman and R. A. Robinson, J . Org. Chem. 35, 3532 (1970). E. E. Smissman, R. A. Robinson, and A. J. Boyer-Matuszak, J . Org. Chem. 35,3822 (1970). E. E. Smissman and J. W. Ayres, J. Org. Chem. 36,2407 (1971). 286 E. E. Smissman, J. W. Ayres, P. J. Wirth, and D. R. Abernethy, J . Org. Chem. 37, 3486 (1972). 2 8 7 K. Stankiewicz and B. Bobranski, Farmaco, Ed. Sci. 33,740 (1978). F. J. Marshall, J . Am. Chem. SOC.78,3696 (1956). J. Knabe, W. Geismar, and C. Urbahn, Arch. Pharm. (Weinheim, Ger.) 302,468 (1969). 290 H. C. Brown and B. C. Subba Rao, J . Am. Chem. Soc. 81,6433 (1959). E. E. Smissman, A. J. Matuszak, and C. N. Corder, J . Pharm. Sci. 53, 1541 (1964). 292 Y.Kondo and B. Witkop, J . Org. Chem. 33,206 (1968). 293 L. Chafetz, T. H. Chen, and R. C. Greenough, J . Pharm. Sci. 62,512 (1973). 294 K. H. Dudley, J. J. Davis, D. H. Kim, and F. T. Ross, J . Org. Chem. 35, 147 (1979). 283

DM

Sec. III.C]

275

BARBITURICACID

'

R a ~ t i o5-29 . ~ ~ Four main products of reduction were isolated for each barbiturate (112; R' = Me, Et; R2 = Ph; R' = R2 = allyl; R3 = H, Me), namely, di- and tetrahydrobarbiturates 113 and 114 when one or two carbonyl groups were reduced to a secondary hydroxyl group, primary alcohols 115, which were formed via the reductive cleavage of the barbituric acid ring, and urea derivatives 116, which were formed simultaneously with the primary alcohols from the rest of the ring298(Scheme 8). Additionally, the reduction of l-methyl-5,5-diallylbarbituricacid led to formation of small amounts of 117.299 R'

R'

-'R

1

(IlSa)

Iff21

flQb)

NaBH,

OH

RIL OH

R'

(115)

+

NH.-

CO-NH-R'

NaBH4

-

R'

NH , Re

OH ( 414 1

( I f 61

(114a) HO trans (114b) HO cis

SCHEME8. CI+CH-CHt

C h d k CHt (117)

Studies on 112 (R' = allyl, R2 = 2'-hydroxypropyl, R3 = H) indicated the formation of 114a on reduction with sodium borohydride in absolute ethanol for 90 min.300 Under the same conditions, different barbituric acids were reduced, yielding trans- and ~ i s - 4 , 6 - d i o l s . ~ ~ ~ * ~ ~

'

M. Rautio, Farm. Aikak. 83, 123 (1974). M. Rautio, Farm. Aikak. 84,143 (1975). 297 M. Rautio, Farm. Aikak. 84, 155 (1975). 298 M. Rautio, Ann. Acad. Sci. Fenn., Ser. A2 178, 1 (1976). 299 M. Rautio, A. Hesso, and E. Rahkamaa, Arch. Pharm. (Weinheim, Ger.) 314,622 (1981). '0° M. Rautio and K. Vuori, Acta Chem. Scand., Ser. B B34,770 (1980). 301 M. Rautio, Acta Chem. Scand., Ser. B B33,770 (1979). 295

296

276

JACEK T. BOJARSKI

et

al.

[Sec. 1II.D

The treatment of 5-acylbarbituric acids (118; R = Pr, i-Pr, pentyl, pentadecyl; R’ = H, Me) with sodium cyanoborohydride in acetic acid resulted in the reduction of the exocyclic carbonyl group only and the formation of the corresponding alkyl barbiturate^."^

D. STABILITY OF THE PYRIMIDINE RING Hydrolytic degradation of medicinal barbiturates and their salts is an important but undesirable process from the pharmaceutical point of view. A brief account has been given by Doran,’ and Bojarski reviewed the literature up to 1967.’03 The products of hydrolytic ring opening and possible pathways of their formation via hydrolytic and decarboxylation processes, summarized in Scheme 9, are dependent on the reaction conditions, i.e., temperature, pH, pressure, and the type of barbituric acid derivative. The sequence 119 + 120 --t 121 involves 1-6 ring opening and is the most common degradation pathway for aqueous solutions of 5,5-di- and 1,5,5-trisubstituted barbiturates with hydrocarbon s u b s t i t ~ e n t s . ~ * ~ ~ ” ~ The diamides of malonic acid (124) confirm the 1-2 ring opening and were also detected among the degradation p r o d ~ c t s . ~ ~ 2-3 ~ * ’ ~Compounds *~~

’

R. A. Schultz, J. Obaza, and F. X. Smith, J . Org. Chem. 45,4606 (1980). J. Bojarski, Wiad. Chem. 23,399 (1969). 304 H. Aspelund and B. Eklund, Acta Acad. Abo., Ser. B.21, No. 3 (1957). 305 F. Fretwurst, Arzneim-Forsch. 8,44 (1958). 306 A. J. Kapadia, J. E. Goyan, and J. Autian, J . Am. Pharm. Assoc. 48,407 (1958). 307 J. Knabe and H. Junginger, Dtsch. Apoth.-Ztg. 111, 1415 (1971). 308 H. V. Maulding, J. Nazareno, J. Polesuk, and A. Michaelis, J . Pharrn. Sci. 61,1389 (1972). M. Rautio, Farm. Aikak. 83,131 (1974). 310 A. B. Hansen and S. S . Larsen, Arch. Pharm. Chem., Sci. Ed. 3,7 (1975). 31’ T. Hermann, Pharmazie 31,368 (1976). 312 J. Bojarski, W. Kahl, and M. Melzacka, Rocz. Chem. 39,875 (1965). 3 1 3 H. Aspelund, Acta Acad. Abo., Ser. B 29, No. 8 (1969). 314 J. Bojarski, Rocz. Chem. 47,1417 (1973). 3 1 5 J. Leslie, J . Pharm. Sci. 68,639 (1979). 302 C. F. Nutaitis, 303

Sec. III.D]

277

BARBITURIC ACID

'I'

9' R\

-R t

R' I

P/cHcON-cOOH

R./

(122 I

CHCONH-R' 123 )

X I P-NH-c-NH-R'

123 were isolated when the hydrolytic degradation of barbiturates was carried out under elevated pre~sure.~'N-Methyl-N-(2-phenylbutyryl)carbamicacid (125), corresponding with 122 (R' = Et, R2 = Ph, R3 = Me), was isolated among the products of alkaline hydrolysis of N-acetyl, N-benzoyl, and N-pnitrobenzoyl derivatives of 5-ethyl-1-methyl-Sphenylbarbituricacid, and its structure was confirmed by decarboxylation to 127 and by independent synthesis of methyl ester 126 shown in Scheme The unusual stability of 125 was due to inter- and intramolecular hydrogen bonding as evidenced by IR studies.318 Me

(125).

ME 5 Et'CHCOA-COOh Ph/

1126)

-

Et'CHCOCI

+

Ph'

Et \ CHCONH-Me Ph' (127)

SCHEME 10

M. Freifelder, A. 0.Geiszler, and G. R. Stone, J . Org. Chem. 26,203 (1961). J. Bojarski, W. Kahl, and M. Melzacka, Rocz. Chem. 40,1465 (1966). 31s W. Waclawek and J. Bojarski, Rocz. Chem. 43,407 (1969).

317

Ilr NI H C O O k

278

JACEK T. BOJARSKI et al.

[Sec. 1II.D

Kinetic studies showed that undissociated and monoanionic barbiturate acid hydrolyzed with different pseudo-first-order rates at constant pH.308,311,315.319-337 The log k-pH profiles for hydrolysis of barbiturates in neutral and alkaline media indicate that degradation takes place by hydroxide ion attack on the undissociated and monoanion species or by the kinetically equivalent attack of water on the mono- and dianion forms.319,326,329-331,338 Several authors pointed out that this relatively simple kinetic model is complicated by some reversible processes. Eriksson presented kinetic evidence for the reversible reaction between the undissociated form of barbiturates and The existence of mono-, di-, its tetrahedral hydroxide ion and trianionic tetrahedral addition intermediates formed from the monoanionic form of barbituric acid in alkaline medium has been postulated by Khan and Khan.336Garrett et d.demonstrated. a reversible reaction between the product of hydrolysis 120 and the parent barbiturate 119 in the case of barbital.329This finding was confirmed342and also demonstrated for other barbiturate^.^'^^^^ Reversible reactions have been shown to exist in the hydrolysis of tetrasubstituted barbiturate^."^.^^^ Leslie reported a biexponential degradation rate of 1,3-dimethylphenobarbitalin 0.02-0.32 M KOH, but at lower and higher OH- concentrations it approached first-order 59330

kinetic^.^

’

Hasegawa, K.Ikeda, and T. Matsuzawa, Chem. Pharm. Bull. 6, 36 (1958). K. Ikeda, Chem. Pharm. Bull. 8,504 (1960). 3 2 1 J. E. Goyan, Z. I. Shaikh, and J. Autian, J . Am. Pharm. Assoc. 49,627 (1960). 322 F. Tishler, J. E. Sinsheimer, and J. E. Goyan, J. Pharm. Sci. 51,214(1962). E. Zajta, Acta Pharm. Hung.32, 129 (1962). 3 2 4 S . 0.Eriksson and A. Holmgren, Acta Pharm. Suec. 2,293 (1965). 3 2 5 S. 0.Eriksson, Acta Pharm. Suec. 2,305 (1965). 326 E. Goto, T. Furukawa, and S . Goto, Arch. Pract. Pharm. 27,311 (1967). 3 2 7 S . S. Larsen and V. G. Jensen, Dan. Tidsskr. Farm. 43,47 (1969). 328 H. V. Maulding and M. A. Zoglio, J . Pharm. Sci. 60,40 (1971). 329 E. R. Garrett, J. T. Bojarski, and G. J. Yakatan, J . Pharm. Sci. 60, I145 (1971). 330 J. Bojarski, Rocz. Chem. 48,619 (1974). 3 3 ’ T. Hermann, Pharmazie 29,453 (1974). 332 H. V. Maulding, J. Polesuk, and D. Rosenbaum, J . Pharm. Sci. 64,272 (1975). 333 A, B. Hansen and S . S . Larsen, Arch. Pharm. Chem., Sci. Ed. 3,7 (1975). 334 T. Hermann, Pharmazie 31,618 (1976). 335 T. Hermann and M. Piechowiak-Gwiazdowska, Pol. J. Pharmacol. Pharm. 28,205 (1976). 336 M. N. Khan and A. A. Khan, J.C.S. Perkin I, 1009 (1976). 337 S. Asada, M. Yamamoto, and J. Nishijo, Bull. Chem. Soc. Jpn. 53,3017 (1980). 338 S . 0. Eriksson, Sci. Pharm. 2,255 (1967). 339 S. 0.Eriksson and C. G. Regardh, Acta Pharm. Suec. 5,457 (1968). 340 S . 0.Eriksson, Acta Pharm. Suec. 6,139 (1969). 3 4 1 S . 0.Eriksson, Acta Pharm. Suec. 6,321 (1969). 342 L. A. Gardner and J. E. Goyan, J . Pharm. Sci. 62, 1026 (1973). 343 J. Bojarski, J. Mokrosz, and M. Klimczak, Pol. J. Chem. 52, 1457 (1978). 319 J.

320

”’

Sec. III.D]

BARBITURIC ACID

279

The hypothesis that the 1-2 hydrolytic opening of the barbiturate ring is associated with the undissociated form was not fully supported by experimental e ~ i d e n c e . ~ ”The . ~ ~1-6 ~ ring opening is favored in all barbiturates and the 1-2 opening is of minor importance, except when some steric factors, such as a bulky C-5 substituent or the presence of some N-substituents, inhibit the 1-6 alternative.329 The results of other studies support this view,305,308,312*31 3 ~ 3 4 4but its definite and detailed experimental proof is still lacking. The effect of substituents on the stability of barbiturates has been widely investigated, and many qualitative and quantitative data allow some general conclusions. The steric influence of C-5 substituents exerts a dominant effect on the rate of hydrolysis. Elongation of the carbon side chain, especially a substitution of a methyl by an ethyl group, decreases the rate of hydrolysis.307.324.325,329,345 Similar effects are produced by branching of the chain, introduction of a bromine atom into especially at the a position,324,325*329B346 the side hai in,^^^,^^^ and enlargement of the substituent ring Larger C-5 substituents shield the ring against nucleophilic attack. Thus for barbiturates where such steric shielding is impossible (5,5-dimethyl- and spirocycloalkyl- 1’,5-barbituric acids), rate constants for hydrolysis are markedly higher and activation energies are lower than those for 5,5-dialkylbarbit u r a t e ~ Electronic .~~ effects are responsible for the enhancement of the hydrolysis rate when unsaturated or aromatic substituents are attached to the

c-5 atom.305,307.324-326,329,34S

N-Methyl-5,5-disubstituted barbiturates are less stable in alkaline medium than their nonmethylated analogs,344~347~348 but this may not be true when the ionization of the molecule is taken into account and similar species are compared. Although the rate constants for the hydrolysis of undissociated and monoanionic forms of 5,5-diallylbarbituric acid are almost twice as high as those for l-methyl-5,5-diallylbarbituricacid hydrolyzed under the same conditions,341in the case of 5,5-diethylbarbituric acid the corresponding rate constants were higher for the N-methyl analog.329It was claimed that the N phenyl substituent decreases the stability of the barbituric acid ring more than the N-methyl while a similar effect of the N-benzoyl group is stronger than that of the N-phenyl ~ u b s t i t u e n t . ~The ~ ’ higher the electronegativity of the N-acyl substituent, the lower was the stability of the H. Aspelund, Acta Acad. Abo., Ser. B 29, No. 7 (1969). C. Stainier, J. Bosly, F. Dutrieux, and R. Stainier, Pharm. Acta Helv. 38, 587 (1963). 346 J. M. A. Sitsen and J. A. Fresen, Pharm. Weekbl. 109,61 (1974). 3 4 7 H. Ruhkopf, Ber. Dtsch. Chem. Ges. 73,938 (1940). 348 H. Aspelund and K. Makela, Acta Acad. Abo. Ser. B 23, 1 (1963). 349 B. Bobranski and R. Wojtowski, Rocz. Chem. 40,1707 (1966). 3 5 0 H. Sladowska, Rocz. Chem. 46,857 (1972). 344

345

280

[Sec. 1II.D

JACEK T. BOJARSKI et al.

appropriate N-acyl derivative of 5-ethyl-1-methyl-5-phenylbarbituric acid.31 The N-substituents significantly influence the ability of the barbituric acid ring with a 5-p-hydroxypropyl substituent to isomerize in alkaline medium to the corresponding allophanyl-y-valerolactone as the result of the C-N bond fi~sion.~” For 1,5,5-trisubstituted derivatives (128) there are two possibilities of ring opening, 1-6 or 3-4, leading to the isomeric derivatives of acetylurea 129 or 130. But ring opening yields only 130 for N-alky1,305*325 substituents. a r ~ l , ~and ’ acy13

’

293

d

(129)

For 1,3,5,5-tetrasubstituted barbiturates the 1-6 versus 1-2 or 3-4 ring opening depends on the nature of the substituents and on hydrolysis condition^.^'^^^'^^^^^ 2-Thiobarbiturates are less stable than their 2-0x0 analogs in an alkaline medium.304~329~355~356 The barbituric acid ring is quite stable in an acidic medium (undissociated m ~ l e c u l e )and ~ the only barbiturates whose ring opens under these conditions are 5-allyl-5-(2‘hydroxypropy1)barbituricacid ( p r o ~ i b a r b a I ) ~ ~ ’and - ~ ’ l-benzoyl-5-ethyl-5~ phenylbarbituric acid (ben~onal).~ 53 Sayer and DePecol reported that 131 undergoes hydrolysis in aqueous acid and base solutions, yielding 132, 133, and 134, respectively.360 Ring conr

7

H

+ L

&-CHO

-1

SCHEME11

B. Bobranski, Farmaco, Ed. Sci. 27,429 (1972). M. Melzacka and W. Kahl, Rocz. Chem. 45, 1091 (1971). 353 M. Paluchowska, L. Ekiert, K. Jochym, and J. Bojarski, Pol. J . Chem. 57,799 (1983). 3 5 4 M. Melzacka and W. Kahl, Rocz. Chem. 43, 1199 (1969). 355 F. I. Carroll and A. Philip, J . Med. Chem. 14,394 (1971). 356 J. Bojarski, Rocz. Chem. 48,619 (1974). R. Wojtowski, Arch. Immunol. Ther. Exp. 13, 127 (1965). 358 T. Hermann and J. Kulbiej, Acta Pol. Pharm. 36,51(1979). 359 T. Hermann, J. Mokrosz, and J. Bojarski, Pol. J . Pharmacol. Pharm. 32,807 (1980). 360 J. M. Sayer and M. DePecol, J . Am. Chem. Soc. 99,2665 (1977). 35’

352

”’

Sec. III.D]

28 1

BARBITURIC ACID

tractions of substituted 5-bromobarbiturates to 4-oxazolidinone and hydantoin systems under alkaline conditions were also described, but the mechanism of these reactions is not fully elucidated.361 Hydrolysis of 5-arylidenebarbiturates (5) proceeds according to Scheme 1l.24 Kinetic studies revealed the isoentropic character of this rea~tion.~~”~~~ 0

b

k

0

M

a

+

0

1133)

ne

(1541

Hydrolysis was the accompanying reaction to the reduction of 5 3 diallylbarbituric acid with NaBH4309*364 and to the N-methylation of different barbiturate^.^^^-^^' The effects of different protecting agents and solubilizers on the stability of medicinal barbiturates also deserve close attention because of their pharmaceutical i m p ~ r t a n c e . ~ ~ ~Th * ~e ~sta*-~’~ bility of barbiturates in frozen systems has also been inve~tigated.~~’*~’~’~~’ 361

362

H.Aspelund, Acta Acad. Abo. Ser. B 27, No. 9 (1967). B. A. Ivin, A. I. Dyachkov, I. M. Vishnyakov, and E. G. Sochilin, Zh. Org. Khim. 11, 1550 (1975).

363

A. I. Dyachkov, B. A. Ivin, I. M. Vishnyakov, and E. G. Sochilin, Zh. Org. Khim. 13, 1758 (1977).

M. Rautio and J. Halmekoski, Farm. Aikak. 83,83 (1974). J. Bojarski, W.Kahl, and M. Melzacka, Rocz. Chem. 42.41 (1968). 366 R. M. Thompson and D. M. Desiderio, Org. Mass Spectrom. 7,989 (1973). 367 R. D. Budd, J. Chromatogr. 237, 155 (1982). 368 B. M. Colombo and P. Causa, Farmaco, Ed. Pract. 25,95 (1970). 369 B. M. Colombo, P. Primavera, and D. Lojodice, Farmaco, Ed. Pract. 25,241 (1970). 370 S. A. Khalil, M. A. Moustafa, V. F. Naggar, and M. M. Motawi, Can. J . Pharm. Sci. 7, 109 364 365

(1972).

E. Pawelczyk and B. Knitter, Acta Pol. Pharm. 28,297 (1974). I. Kojo, S.Awazu, and M. Hanano, Chern. Pharm. Bull. 22,864 (1974). 373 E. Izgu and I. Ababeyoglu, J. Fac. Pharm. Ankara Uniu. 6,30 (1976). 374 R. C. Kelly, J. C. Valentour, and I. Sunshine, J . Chromatogr. 138,413 (1977). 375 S. Borodkin, L. Macy, G. Thompson, and R. Schmits, J . Pharm. Sci. 66,693 (1977). 376 S. S. Larsen and V. G. Jensen, Dan. Tidsskr. Farm. 44,21(1970). 377 A. B. Hansen and S. S . Larsen, Arch. Pharm. Chem., Sci. Ed. 4,21 (1976). 371

372

282

[Sec. 1II.E

JACEK T. BOJARSKI et a!.

E. PHOTOCHEMICAL REACTIONS Only a few workers have reported photochemical reactions of barbiturates. Otsuji et al. found that hydrolysis of 5,5-diethylbarbituric acid, in alkaline solution, is accelerated by UV (254 nm) light.378 Investigations of 5 3 dialkylbarbituric acid photolysis, carried out by Bojarski and cow o r k e r ~ , questioned ~ ~ ~ * ~ a~ previous ~ photohydrolytic mechanism378 and implicated the photochemical ring-opening reaction within the malonyl moiety with the isocyanate dt ivative 135 as an intermediate379(Scheme 12).

OpO R

I

R

SCHEME12. X

= NH,,

NHCOX

OEt, NMe,, NCH,CH,, OH (with subsequent decarboxylation)

Moreover, the isocyanate photoproduct was found to undergo hydrolysis at both the isocyanate and adjacent carbonyl groups, producing urea and amide derivatives, re~pectively.~"The exact position of ring opening at the C-4-C5 bond was evidenced by the formation of 137 during photolysis of 136 (R = Et, Ph) but the formation of hydantoin derivative 138 by an elimination

He

ME

of the CO molecule from the barbituric acid ring was also o b ~ e r v e d . ~ ' ~ . ~ ~ ~ Similar photochemical contractions of the barbituric acid ring were described for 5-methylbarbituric acid3*j and 5,5-dihydroxybarbituric Thus the photochemical ring opening of monoanions of barbiturates occurs at the Y. Otsuji, T. Kuroda, and E. Imoto, Bull. Chem. Soc. Jpn. 41,2713 (1968). H. Barton, J. Bojarski and J. Mokrosz, Tetrahedron Lett. 23,2133 (1982). H. Barton, J. Mokrosz, J. Bojarski, and M. Klimczak, Pharmazie 35, 155 (1980). H. Barton, PhD. Thesis, Jagiellonian University, Krak6w (1982). H. Barton, A. Zurowska, J. Bojarski, and W. Wejna, Pharmazie 38,268 (1983). 3 8 3 E. Fahr, P. Fecher, G . Roth, and P. Wuestenfeld, Angew. Chem. 92,858 (1980). 384 Y. Otsuji, S. Wake, and E. Imoto, Tetrahedron 26,4139 (1970). 378

379

"'

Sec. III.F]

BARBITURIC ACID

283

ionized side of the pyrimidine ring, that is, at the side other than that found in the hydrolytic pathway (see Section 111,D). Kinetic investigations showed that the photochemical ring-opening reaction depends on the nature of the C-5 substituents, i.e., the quantum yield is the highest for short alkyl substituents and decreases for long alkyl, unsaturated, and aromatic ones. Moreover, the quantum yield of photolysis is higher for the monoanion forms than for the undissociated m o l e ~ u l e s . ~ ~ ~ * ~ ~ During the photolysis of barbiturates with a-branched substituents at C-5, the ring-opening reaction is accompanied by dealkylation of these substituents.385-387The elimination of the allyl group has also been observed in the On the case of photolysis of 5-allyl-5-(l’-methylbutyl)barbituric other hand, comparative studies on hydrolysis and photolysis of 5-allyl-5-(2’hydroxypropy1)barbituric acid showed only an increase of the rate of hydrolysis by UV light with no differences in the isolated p r o d ~ c t s . ~ ~ ~ * ~ ~ ~ Photooxidation at the 6-position of the cyclohexene ring was observed for 5-(l’-cyclohexen-l’-yl)-5-ethylbarbituric a ~ i d . The ~ ~ influence ~ . ~ ~of ~Xray,391-394gamma ray,395*396 and electron397irradiations on barbituric acid derivatives was also investigated.

F. OTHERREACTIONS During cyclization of 5,5-di- and/or 1,5,5-trisubstituted barbiturates, formation of bicyclo compounds was observed as a result of intramolecular 0-alkylation. Thus 139 (R = allyl, R’ = Ph, bPr; R = Ph, R’ = 2‘bromopropyl) formed furanopyrimidine 140, and 139 (R = Ph, R’ = 3’bromopropyl) formed pyranopyrimidine 141.283.284 Similarly, cyclization of some N-(3’-halopropyl)barbiturates led to products of intramolecular 0alkylation at the 2- or 6-carbonyl g r o ~ p(Eq. ~ 8). ~ ~ , ~ ~ ~ J. Mokrosz, M. Klimczak, H. Barton, and J. Bojarski, Pharmazie 35,205 (1980). J. Mokrosz and J. Bojarski, Pharmazie 37,768 (1982). 387 H. Barton and J. Bojarski, Pharmazie 38,630 (1983). 388 J. Mokrosz, A. Zurowska, and J. Bojarski, Pharmazie 37,832 (1982). 389 G. Willems, D. De Backer, R. Bouche, and C. De Ranter, Bull. Sac. Chim. Belg. 82,803 (1973). 390 R. Bouche, M. Draguet-Brughmans, J. P. Flandre, C. Moreaux, and M. van Meerssche, J. Pharm. Sci. 67, 1019 (1978). 391 R. A. Haak and B. Benson, J. Chem. Phys. 55,3693 (1971). 392 P. Guetierrez and B. Benson, J. Chem. Phys. 60,640 (1974). 393 P. Guetierrez and B. Benson, Radiat. Res. 58, 141 (1974). 394 J. Huttermann and G . Schmidt, J. Magn. Resan. 21,221 (1976). 395 B. Benson and L. Erich, Radiat. Res. 86,411 (1981). 396 C. Houee-Levin, M. Gardes-Albert, C. Ferradini, and J. Pucheault, Radial. Res. 88,20 (1981). 397 R. Boyum, E. Sagstuen, and T. Henriksen, Radial. Res. 80,233 (1979). 385

386

284

JACEK T. BOJARSKI et a/.

[Sec. 1II.F

5,5-diallylbarbituric acid undergoes cyclization in the presence of Pd(II), and spiro compound 142 is formed.j9*

tie (142)

Although the reaction of barbiturates with saturated aldehydes normally yields the alkylidene compounds (Section III,A), condensation of 143 (R = R = H, Me) with both enantiomers of 144 produced optically pure tricyclic (Eq. 9). dihydr~pyrans~~’

399

R. Grigg, T. R. B. Mitchell, and A. Ramasubbu, J.C.S. Chem. Commun., 666 (1979). L. F. Tietze and G . V. Kiedrowski, Tetrahedron Lett. 22,219 (1981).

Sec. III.F]

28 5

BARBITURIC ACID

(l43)

(144)

The treatment of 5-phenyl-5-(3’-bromopropyl)barbituric acid (145) with ammonium hydroxide yields 3-phenyl-3-allophanyl-2-piperidon.The reaction begins with the ammonolysis of 145; and then the resultant primary amino function attaches to the C-6 or C-4 carbonyl group of the ring with ring opening to yield 146, which then hydrolyzes to 147.4005-Phenyl- and 5allyl-5-(2’-hydroxypropyl)barbituric acids undergo similar intramolecular isomerization and ct-phenyl-a-allophanyl-y-valerolactonesare formed,

(W)

(I660

(li?)

N-Hydroxyacyl barbiturates isomerize to compounds of hemiketal acid isomstructure. l-Benzyl-3-a-hydroxypropionyl-5,5-diethylbarbituric erizes spontaneously to hemiketal 148, in anhydrous THF during PdO, catalytic hydrogenation under normal pressure.404 On the other hand, the y:Ph

“YNYO

E. E. Smissman and P. J. Wirth, J . Org. Chem. 40,1576 (1975). B. Bobranski, D. Prelicz, L. Syper, and R. Wojtowski, Rocz. Chem. 37,795 (1963). 402 H. Wittekind and B. Testa, J . Chromatogr. 179,370 (1979). 403 0. Lafont, B. Lambrey, C. Jacquot, J.-R. Rapin, P. &Athis, and D. de Lauture, Eur. J . Med. Chem. 14, 143 (1979). 404 B. Bobranski and H. Sladowska, Rocz. Chem. 46,451 (1972). 400

401

286

[Sec. 1II.F

JACEK T. BOJARSKI et al.

hydrogenation of 1,3-bis(cr-benzyloxypropionyl)-5,5-diethyl-2-desoxybarbituric acid under the same conditions gave two isomers, which had the structures of 12-membered cyclodepsipeptides 149a and 149b.405 / \

/ \

co

0

NH

CO \ /Et

NH

CO

co

0

I

c/q

I

/

I

co I

1

NH

CO

NH

0

CO \ /Et

I

\ /

,c.

CH,

.I‘

k

d

(1490) ( C i s )

\

CHS

(149b)(trans)

The isomerization with cleavage of the barbituric acid ring depends on substituents at the nitrogen atom^.^^^^^^^*^^^ Introduction of a benzoyl group acid enables into the 3-position of l-o-hydroxyphenyl-5,5-dipropylbarbituric this compound to isomerize to the correspondent depsipeptide (150), whereas l-o-hydroxyphenyl-3-phenyl-5,5-dipropylbarbituric acid does not isomerize. 509408

(150)

The ring contraction of barbiturates is observed in the course of hydrolytic degradation (Section 111,D). N-Substituted barbiturates 151 (R’ = RZ = alkyl, R 3 = H) yield the 5-substituted oxazolidine-2,4-dione 152,and N,Nunsymmetrically substituted barbiturates yield a mixture of both 152 and 153. 5-Bromobarbituric acid and its derivatives give a mixture of iminooxazolidin4-one and h y d a n t ~ i n . ~ ’ ~ 1-Aminobarbituric acid (154; R = H, Me, Et, Pr, Bu) undergoes an B. Bobranski and H. Sladowska, Rocz. Chem. 46,459 (1972). B. Bobranski and H. Matczak, Rocz. Chem. 48,2137 (1974). 407 H. Sladowska, Farmaco, Ed. Sci. 30, 159 (1975). 408 H. Sladowska, Rocz. Chem. 46,615 (1972). 409 H. C . van der Plas, “Ring Transformation of Heterocycles,” Vol. 2, p. 125. Academic Press, New York. 1973. 40s

406

Sec. III.F]

287

BARBITURIC ACID

(lS1)

(l521

(153)

isomerization in acidic medium to 2-(5-oxo-4,5-dihydro-lH-1,2,3-triazol-3-y1) aliphatic acids (156). Reaction was found to be initiated by a simple, acidcatalyzed hydrolysis of the C-6-N-1 amide bond; then intermediate 155 cyclized to the triazole ring system.41o

(155)

(1511

(156)

Barbiturates also form crystalline intermolecular complexes. Complexes of 5,5-diethylbarbituric acid with acetamide;l' urea,412 imidazole:13 2,4-diamino-5-(3,4,5-trimetoxybenzyl)pyrimidine~'4and N-methyl-2-pyridone415 have a 1:1 composition. 5-Ethyl-5-(3'-methylbutyl)barbituric acid with salicylamide forms the 1:l complex as The former gives a crystalline 1:2 complex with 2-amin0pyridine.~~'l-Methyl-5,5-diethylbarbituric acid also forms 1:1 complexes with dimethylacetamide and 9-eth~ladenine.~~' The structures of the inclusion complexes of barbiturates with cycloheptaamylose419 and with P-cy~lodextrin'~ were investigated in detail. Moreover, there are several examples of complexation of barbiturates with C U ( I I ) , ~ ~CO(II):'~ ' * ~ ~ ~ Ag(I),423 and pentachloronitN. W.Jacobsen, B. L. McCarthy, and S. Smith, Aust. J . Chem. 32,161 (1979). L N . Hsu and B. M. Craven, Acta Crystallogr., Sect. B B30,974 (1974). 412 G. L. Gartland and B. M. Craven, Acta Crystallogr., Sect. B B30,980 (1974). 413 L N . Hsu and B. M. Craven, Acta Crystallogr., Sect. B B30,988,(1974). 414 N. Shimizu, S. Nishigaki, Y.Nakai, and K. Osaki, Acta Crystallogr., Sect. B B38,2309 (1982). 41s I.-N. Hsu and B. M. Craven, Acta Crystallogr., Sect. B B30,998 (1974). 416 I.-N. Hsu and B. M. Craven, Acta Crystallogr., Sect. B B30,843 (1974). 417 I.-N. Hsu and B. M. Craven, Acta Crystallogr., Sect. B B30,994 (1974). 418 H. Loth and D. Beer, Arch. Pharm. (Weinheim, Ger.) 304,65 (1971). 419 A. L. Thakkar and P. V. Demarco, J . Pharm. Sci. 60,652 (1971). 420 J. Morvay, J. Csaszar, and V. Nikolasev, Acta Pharm. Hung. 39, 193 (1969). 421 J. Morvay, J. Szabo, and G. Kozepesy, Acta Pharm. Hung. 39,208 (1969). 422 J. Morvay, J. Csaszar, and V. Nikolasev, Acta Pharm. Hung. 39,202 (1969). 423 A. Bult and H. B. Klasen, Pharm. Weekbl. 110,533 (1975). 424 M. D. Pundlik and R. W . Ramachandra, Khim. Geterotsikl. Soedin., 837 (1976). 410

41

288

JACEK T. BOJARSKI et al.

[Sec. IV

r ~ s y l r u t h e n a t eInvestigations .~~~ of the interaction between barbiturates and polyethylene glycol 4000 show that the hydrogen bond is responsible for the formation of these complexes.426

IV. Analytical Methods for Barbiturates Analysis of barbiturates is closely associated with their use, misuse, and abuse as therapeutic agents and is of deep interest to clinical and forensic analysts and toxicologists. The results may be of value for monitoring the therapy or treatment of patients in cases of overdosing and accidental or criminal poisoning with barbiturate drugs. A review of the detection and estimation of barbituric acid derivatives, published in 1962, contains 500 reference^,"^' and since that time hundreds of papers have been published on these subjects. Several reviews and monographs present information about different analytical methods, their applications, and limitations for barb i t u r a t e ~ . ~ ~Classical * ~ ~ ’ color reactions for the identification of barbiturates with cobalt(I1) salts (Parri reaction), copper(I1) salts + pyridine (Zwicker reaction), and Hg(I1) salts + dithisone are still used and being improved.438443Auterhoff and Streck elucidated the chemical nature of the S. Sueur, C. Bremard, and G. Nowogrocki, Bull. Soc. Chim. Fr., 1051 (1976). B. L. Chang, N. 0.Nuessle, and W. G. Haney, J. Pharm. Sci. 64,1787 (1975). 4 2 7 G. Schmidt, in “Methods of Forensic Science” (F. Lundquist, ed.), Vol. 1, p. 373, Wiley (Interscience),New York, 1962. 428 A. S. Curry, in “Toxicology” (C. P. Stewart and A. Stolman, eds.), Vol. 2, p. 153 Academic Press, New York, 1961. 425

426

F. Amelink, “Rapid Microchemical Identification Methods in Pharmacy and Toxicology.” Netherlands Univ. Press, Amsterdam, 1962. c30 D. M. Baer, Am. J . Clin. Pathol. 44, 114 (1965). 4 3 1 E. G. C. Clarke ed., “Isolation and Identification of Drugs.” Pharm. Press, London, 1975. 432 C. C. Fulton, “Modern Microcrystal Tests for Drugs,” p. 134. Wiley (Interscience), New York, 429

1969.

K. Macek, ed., “Pharmaceutical Application of Thin Layer and Paper Chromatography,” p. 213. Elsevier, Amsterdam, 1972. 434 N. C. Jain and R. H. Cravey, J. Chromatogr. Sci. 12,228 (1974). 43s J. Sunshine, ed., “Methodology for Analytical Toxicology,” p. 34. CRC Press, Cleveland, Ohio, 433

1975.

R. K. Miiller, “Die toxikologisch-chemische Analyse,” p. 239. Steinkopf, Dresden, 1976. 4 3 7 W. Sadee and G. C. M. Beelen, “Drug Level Monitoring,” p. 148. Wiley, New York, 1980. 438 D. Bruijn, Clin. Chim. Acta 53,385 (1974). 439 M. J. de Faubert-Maunder, Analyst 100,878 (1975). 440 F. Pehr, Clin. Chem. (Winston-Salem,N.C.) 21, 1609 (1975). 441 A. Bult, Pharm. Weekbl.lll, 157 (1976). 442 F. Pehr, Clin. Chem. (Winston-Salem,N.C.) 25, 1339 (1979). 443 A. Osman and R. Abu-Eittah, J. Pharm. Sci. 69,1164 (1980). 436

Sec. IV]

BARBITURIC ACID

289

color reaction of 5-phenyl-substituted barbiturates in concentrated sulfuric acid with sodium nitrite, formaldehyde,and piperonal. A A complex between the phenyl ring and the nitrosyl cation and the formation of carbocations and quinone structures without methylene or oxymethylene groups were found responsible, respectively, for these reactions.444 Spectroscopic methods (cf. Section I1,B) have been extensively used for identification and quantitation purposes. Highly sensitive luminescence methods were particularly usefu1,53~56*61-6’ however, in UV absorption spectroscopy some interferences have been observed.445448 Various chromatographic techniques are among the most important separation, identification, and determination methods for barbiturates, and only sample papers or reviews will be mentioned. De Zeeuw provided a survey on paper and thin-layer chromatography, collecting useful data on R , values in different chromatographic systems.449In recent years, TLC techniques replaced paper chromatography to a significant degree because of high sensitivity and short time of analysis. Many improvements have been proposed in chromatographic systems for barbiturates, including the use of reversed phases, visualization reagents, and densitometry of spots for quantitative r e s ~ l t sGas . ~chromatography ~ ~ ~ ~ of barbiturates as either the free acids or their derivatives obtained by direct on-column reactions was H. Auterhoff and R. Streck, Arch. Pharm. (Weinheim,Ger.) 309,988 (1976). R. N. Gupta and P. M. Keane, Clin. Chem. (Winston-Salem,N.C.) 19, 1318 (1973). 446 P. Jatlow, Am. J. Clin. Pathol. 59, 167 (1973). 447 G. B. Schumann, Am. J . Clin. Pathol. 66,823 (1976). 448 G. C. Khan, V. D. Goldberg, R. A. Khan, and P. T. Lascelles, Clin. Chem. (Winston-Salem, N.C.) 23, 1942 (1977). 449 R. A. de Zeeuw, Prog. Chem. Toxicol. 4,59 (1969). 450 K. K. Kaistha and J. H. Jaffe, J . Pharm. Sci. 61,679 (1972). 451 A. B. Hansen and S . S. Larsen, Dan. Tiddskr. Farm. 46,105 (1972). 452 W. Diinges and H. W. Peter, in “Methods of Analysis of Antiepileptic Drugs”(J. W. A. Meijer, ed.), p. 126. Excerpta Medica, Amsterdam, 1973. 453 M. Amin, J. Chromatogr. 101,387 (1974). 454 U. Baeyer and D. Villumsen, J . Chromatogr. 115,493 (1975). 4 5 5 M. Braun, G. Hanel, and G. Heinisch, Sci. Pharm. 43, 168 (1975). 456 D. B. Faber, J . Chromatogr. 142,421 (1977). 45’ J. A. Vinson, J. E. Hooyman, H. Koharched,and M. M. Holmes,J. Chromatogr.140,71(1977). 458 I. C. Dijkhuis, Clin. Chem. (Winston-Salem,N.C.) 23,2171 (1977). 459 J. C. Touchstone, M. F. Schwartz, and S. S. Levin, J . Chromatogr. Sci. 15,528 (1977). 460 R. A. Eittah, A. Osman, and A. El-Behare, Analyst 103,1083 (1978). 461 D. C. Fenirnore, C. M. Davis, and C. J. Mayer, Clin. Chem. (Winston-Salem, N.C.) 24, 1386 444

445

(1978).

L. Ekiert, Z. Grodzinska-Zachwieja, and J. Bojarski, Chem. Anal. 24,1045 (1979). L. Ekiert, Z. Grodzinska-Zachwieja, and J. Bojarski, Chromatographia 13,472 (1980). 464 W. Bress, K.Ziminski, W. M. Long, T. Manning, and L. Lubash, Clin. Toxicol. 16,219 (1980). 465 A. H. Stead, R. Gill, T. Wright, J. P. Gibbs, and A. C. Moffat, Analyst 107, 1106 (1982). 462

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excellently reviewed by Dilli and Pillai,466 and other workers report progress.467471High performance liquid chromatography (HPLC) gained wide acceptance, and numerous studies were devoted to analytical applications of this method to barbiturates.472490 Popova studied analytical applications of gel chromatography to barbiturate^?^ 1-493 and reports on simultaneous use of several chromatographic techniques were also published.494*495 Plasma chromatography was applied as a very sensitive method for qualitative identification of barbiturates at nanogram levels.496 Relatively new but quickly adopted and developed analytical methods for barbiturates are the enzyme and radioimmunoassay techniques.497 The principles and procedures have been r e ~ i e w e d ~ ~ *and - ’ ~comparisons ~ l2 between these and other analytical methods are D. N. Pillai and S . Dilli, J. Chromatogr. 22,253(1981). B.Kinberger, A. Holmen, and P. Wahrgren, J . Chromatogr. 224,449(1981). A. Turcant, A. Premel-Cabic, A. Cailleux, and P. Allain, J . Chromatogr. 229,222 (1982). 469 L. Zoccobillo, G . Cartoni, and L. Lozzi, J. Chromatogr. 230,339 (1982). 470 D. B. Black, H. Kolasinski, E. G. Lovering, and J. R. Watson, J. Assoc. Of/: Anal. Chem. 65,

466

467

1054 (1982). R. D. Budd and D. F. Mathis, J . Anal. Toxicol. 6,317(1982). 4 7 2 R.W. Roos, J . Pharm. Sci. 61,1979(1972). 473 W. Diinges, G. Naundorf, and N. Seiler, J. Chromatogr. Sci. 12,655 (1974). 474 U. R. Tjenden, J. C. Kraak, and J. F. K. Huber, Z . Anal. Chem. 279, 131 (1976). 475 U.R.Tjenden. J. C. Kraak, and J. F. K. Huber, J . Chromatogr. 143,183(1977). 476 B. B. Wheals and 1. Jane, Analyst 102,625(1977). 477 C. R. Clark and J. L. Chan, Anal. Chem. 50,635(1978). 478 M. C. Bowman and L. G. Rushing, J . Chromatogr. Sci. 16.23 (1978). 479 A. HulsholT, H. Rosenboom, and J. Renema, J. Chromatogr. 186,535(1979). P. C. White, J . Chromatogr. 200,271 (1980). H. R. Schulten and D. Kuemmler, Anal. Chim. Acta 113,253(1980). 1. S. Lurie and S. M. Demchuk, J . Liq.Chromatogr. 4,337(1981). 483 I. S. Lurie and S. M. Demchuk, J. Liq. Chromatogr. 4,357(1981). 484 R. Gill, A. A. T. Lopes, and A. C. Moffat, J. Chromatogr. 226,117 (1981). 485 P. Jandera, J. Churacek, and D. Szabo, Chromatographia 14,7(1981). W. F.Schmidt and L. J. Pennington, J. Pharm. Sci. 71,954(1982). 487 R. N.Gupta, P. T. Smith, and F. Eng, Clin. Chem. (Winston-Salem,N.C.) 28, 1172 (1982). 488 J. C. Kraak and J. P. Crombeen, J . Liq. Chromatogr. 5,273(1982). 489 R. H.Drost, T. A. Plamp, and R. A. A. Maes, J. Clin. Toxicol. 19,303(1982). 490 H. L.Levine, M. E. Cohen, P. K. Duffner, K. A. Kustas, and D. D. Shen,J. Pharm. Sci.71,1281 471

(1982). V. I. Popova, V. P. Kramarenko, and A. M. Medved, Farm. Zh. (Kieu),80 (1976). 492 V. I. Popova, Farm. Zh. (Kieu), 70 (1977). 493 V. I. Popova, Farmatsija (Moscow) 27,34(1978). 494 H. J. Battista and G. Machata, Chromatographia 1, 104 (1968). 495 R. Gill, A. H. Stead, and A. C. Moffat, J. Chromatogr. 204,275(1981). 496 D. S.Ithakissios, J. Chromatogr. Sci. 18,88(1980). 497 S. Spector and E. J. Flynn, Science 174, 1036 (1971). 498 J. Landon and A. C. Moffat, Analyst 101,225(1976). 491

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One of the problems of barbiturate analysis is the isolation of the Extraction is the most compound from biological mat&ia1.427~428~437~44g9513 accepted method, but some assays take advantage of omitting the isolation and purification step. Special attention was devoted to separation and assay of particular barbiturate drugs in combination with other compounds. For example, many methods were devised for the determination of phenobarbital and hydantoin used together in anticonvulsivethe rap^.^ l4 Several procedures were proposed for the determination, of barbiturates along with their metabolites in body The literature about differential thermal analysis methods for barbiturates was collected by Wollman and Brauna5 Polarographic assays have been r e p ~ r t e d , ~ ' and ~ . ~other ' ~ electrochemical methods were also used.518 This short survey is intended only to outline major developments in the analysis of barbiturates. Methods are directed tbward better sensitivity, specificity, rapidity, and discriminating power to meet many demands, but mostly those of trace analysis in blood, urine, and other body fluids and tissues, often in postmortem material, and in combinations with other drugs

499

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R. Cleeland, J. Christenson, M. Usategui-Gomez, J. Heveran, R. Davis, and E. Grunberg, Clin. Chem. (Winston-Salem,N.C.) 22,712 (1976). V. P. Butler, Pharmacol. Rev. 29, 103 (1977). C. B. Walberg, Clin. Chem. (Winston-Salem,N.C.) 20,305 (1974). V. Spiehler, L. Sun, D. S. Miyada, S. G . Sarandis, and E. R. Walwick, Clin. Chem. (WinstonSalem, N.C.) 22,749 (1976). M. Usategui-Gomez, J. E. Heveran, R. Cleelvsad, B. McGhee, Z. Telischak, T. Awdziej, and E. Grunberg, Clin. Chem. ( Winston-Salem, N.C.) 21,1378 (1975). J. J. Turri, Clin. Chem. (Winston-Salem,N.C.) 23, 1510(1977). P. Krugers-Dagneaux, J. T. Kleineihorst, and F. M. F. Olthuis, Pharm. Weekbl. 112, 1169 (1977).

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C. Delmonico, C. Bory, P. Baltassat, and C. Lahet, Clin. Chim. Acta 86, 1 (1978). B. Quednow and M. Walther, Zentralbl. Pharm., Pharmakother. Laboratoriumsdiagn. 118,322 (1979).

K. Aoki, V. Terasawa, and Y. Kurokiwa, Chem. Pharrn. Bull. 28,3291 (1980). T. Nishikawa, M. Saito, and H. Kubo, J . Pharmacobio-Dyn. 3,21 (1980). 'lOI. E. Kovalev, 0. Y. Polevaja, H. P. Danilova, W. I. Ivanov, W. W. Nazarov, and T. I. Uljankina, Khim. Farm. Zh. 15, 14 (1981). 'I1 P. Stoiba and M. Lutovska, Cesk. Farm. 30,111 (1981). 5 1 2 P. A. Mason, B. Law, K. Pocock, and A. C. Moffat, Analyst 107,629 (1982). '13 J. Balkon, D. Prendes, and J. Viola, J . Anal. Toxicol. 6,228 (1982). 'I4 P. Aymard, R. G. Boulu, and F. Sarhan, in "Drug Measurement and Drug Effects in Laboratory Health Science" (G. Siest and D. S. Young, eds.), p. 20. Karger, Basel, 1980. H. Wollmann and V. Braun, Pharmazie 38,5 (1983). 'I6 M. A. Brooks, J. A. F. de Silva, and M. R. Hackman, Anal. Chim. Acta 64, 165 (1973). '17 M. Romer, L. G. Donaruma, and P. Zuman, Anal. Chim. Acta 88,261 (1977). ' I 8 G. D Carmack and H. Freisner, Anal. Chem. 49, 1577 (1977). '08

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In 1962 Schmidt expressed the opinion that “becauseof an overfloodingof the market with synthetic drugs of increased structural complexity, the barbiturates, therapeutically approved for decades, are in danger of being analytically negle~ted.”~” Now we can conclude that his fears were unjustified with respect to the past and most probably will remain so.

V. Correlation Analysis in Barbituric Acid Chemistry Correlation analysis may reveal and discriminate important factors underlying physicochemical properties, chemical reactivity, and/or biological activity. Although observations of qualitative substituent effects on the hypnotic activity of these compounds date back to the work of Nielsen in 1926,’19 quantitative structure-activity relationship (QSAR) studies were initiated by Hansch during the 1960s.520-522Various biological activities of barbiturates strongly depend on their lipophilic character expressed by the octanol-water partition coefficients, while steric and electronic effects of substituents play a minor role. The dependence has parabolic character, and a similar type of relationship was also evidenced for some pharmacokinetic parameters of barbiturate^.^^^^'^^ Partition coefficients were sometimes substituted by chromatographic (retention index, capacity factors) or topological (molecular 27 Some sets of biological activity data connectivity indices) parameters.5z’4 showed linear correlations with such parameters as partition coeffi~ i e n t s ,223 ’ ~ ~ ~34~ chromatographic R , values,’ 5-’3 and molecular

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C. Nielsen, J. A. Higgins, and H. S . Spruth, J. Pharmacol. Exp. Ther. 26,371 (1926). C. Hansch, A. R. Steward, and J. Iwasa, Mol. Pharmacol. 1,87(1965). 5 2 1 C. Hansch and S. M. Anderson, J. Med. Chem. 10,745(1967). C. Hansch, A. R. Steward, S. M. Anderson, and D. Bentley, J . Med. Chem. 11, l(1968). 5 2 3 T.D. Yih and J. M. van Rossum, Biochem. Pharmacol. 26,2117 (1977). 524 T.D. Yih and J. M. van Rossum, J. Pharmacol. Exp. Ther. 203,184(1977). 5 2 5 J. K. Baker, D. 0.Rauls, and R. F. Borne, J. Med. Chem. 22, 1301 (1979). 5 2 6 M. J. M. Wells, C. R. Clark, and R. M. Patterson, J. Chromatogr. Sci. 19,573 (1981). 5 2 7 W. J. Murray, L. B. Kier, and L. H. Hall, J. Med. Chem. 19,573 (1973). K. Kakemi, T. Arita, R. Hori, and R. Konishi, Chem. Pharm. Bull. 15,1534 (1967). 5 2 9 F.Helmer, K. Kiehs, and C. Hansch, Biochemistry 7,2858(1968). 530 H. E. Spiegel and W. W. Wainio, J. Pharmacol. Exp. Ther. 16523 (1969). 5 3 1 C. Hansch, Drug Metab. Rev. 1, 1 (1972). 5 3 2 S.A. Khalil, M. A. Moustafa, and 0.Y.Abdallah, Can. J. Pharm. Sci. 11,121 (1976). 533 N. Kaneniwa, M. Hiura, and S. Nagakawa, C h w . Pharm. Bull. 27, 1501 (1979). 5 3 4 A. C. Moffat and A. T. Sullivan, J. Forensic Sci. 21,239(1981). 5 3 5 M. C.Bonjean, J. Alary, and C. Luu Duc, Chim. Ther. 8,93 (1973).

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connectivity index.538Henry et al. used the logarithms of the retention volume from HPLC of barbiturates to correlate their biological activity, and both parabolic and linear dependences were founda539 Molecular volumes540and fragmental constants541 of 5J-substituents were used by Testa for elegant multiparameter correlations of the affinity for cytochrome P-450 and the hepatic clearance of 32 barbiturates.232The results showed that the factors controlling these processes were lipophilicand steric in nature; only the first effect was anticipated from the same metabolic data analyzed by the single parameter correlation.523 Tong and Lien reported significant correlation between the inhibition of beef-heart submitochondrial NADH oxidation by 14 barbiturates and their corn oil-water partition coefficient. However, when the data for stimulation of rat liver microsomal NADPH oxidation by the same barbiturates were correlated, a good correlation was observed only after exclusion of 5allylbarbiturates, which indicates different activity of the ally1 group in this biotransformation process.542The relationship between molecular structure and duration of depressant effect for 160 5,5-disubstituted barbiturates was investigated by the so-called “Pattern Recognition Technique.” The results were consistent with those obtained via the Hansch approach.543 Although QSAR studies offer a mathematical approach to explain biological activity, semiquantitative correlations of biological effects of barbiturates with their structures are still in use.544-547 Since the lipophilic character was found important for physiological dispositions of barbiturates, several workers investigated the relationship between partition coefficient and structural parameters (Taft’s polar and steric substituents constants, number of C-atoms) of these corn pound^.^^^.^^^ Partitioning of barbiturates was also proved to be a significant factor for their

536

537

J. M. Pla-Delfina, J. Moreno, and A. del Pozo, J. Pharmacokinet. Biopharm. 1,243 (1973). J. M. Pla-Delfina, J. Moreno, J. Duran, and A. del Pozo, J. Pharmacokinet. Biopharm. 3, 115 (1975).

m M. C. Bonjean and C. Luu Duc, Eur. J. Med. Chem. 13,73 (1978). 539 D. Henry, J. H. Block, J. L. Anderson, and G . R. Carlson, J. Med. Chem. 19,619 (1976). 540 A. Bondi, J . Phys. Chem. 68,441 (1964). 541 G . G. Nys and R. F. Rekker, Chim. Ther. 8, 521 (1973). 542 G . L. Tong and E. Lien, J . Pharm. Sci. 65,1651 (1976). 543 A. J. Stuper and P. C. Jurs, J. Pharm. Sci. 67,745 (1978). 544 J. C. Topham, Biochem. Pharmacol. 19,1695 (1970). 545 T. L. Breon and A. N. Paruta, J. Pharm. Sci. 59,1306 (1970). 546 C. Ioannides and D. V. Porke, J . Pharm. Pharmacol. 27,739 (1975). 547 S. Ozeki and K. Tejima, Chem. Pharm. Bull. 25, 1952 (1977). 548 D. J. Lamb and L. E. Harris, J . Am. Pharm. Assoc. 49,583 (1960). 549 K. Kakemi, T. Arita, R. Hori, and R. Konishi, Chem. Pharm. Bull. 15, 1705 (1967).

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transfer p h e n ~ m e n a ,I ~solubility ~~*~~ b e h a ~ i o r , ”HPLC ~ and GLC retention data,” 3--5 and activity coefficients.556 Both partition and adsorption phenomena of barbiturates are involved in the chromatograhic behavior of these compounds, and numerous workers report significant, linear correlations of chromatographic retention data with structural parameters such as the number of carbon atoms in the C-5 s u b s t i t ~ e n t s , 4 connectivity ~ ~ * ~ ~ ~ i n d i ~ e s , ~ and ~ ~molecular ~ ~ ~ vol~ * ~ ~ ~ u m e ~ Correlations . ~ ~ ~ between retention indices from different chromatographic techniques have also been observed, but the results were better within the groups of closely structurally related compounds (e.g., 5,5-dialkyl- or 5alkyl-5-allylbarbit~rates).~~~ The relationship between parameters of adsorption estimated from TLC of barbiturates and a number of different alkyl and alkenyl groups in the C-5 substituents was reported.s63 Nogami et al. investigated absorption of barbiturates by carbon black and related the results to biopharmaceutical data.564*565 The correlations between I3C-NMR chemical shifts of the ring skeletal carbon and the pK, values of 5,5-di- and l-methyl-5,5-disubstitutedbarbiturates were examined by Asada and Nishijo, and a significant relationship has been found only for the C-4 and/or C-6 atoms.125 The logarithms of the second-order rate constants for hydrolysis of 1methyl-5,5-disubstituted barbiturates correlated well with Newman’s “six numbers” for both C-5 s u b s t i t ~ e n t sLinear . ~ ~ ~ relationships between enthalpy and entropy of activation for hydrolysis of barbiturates have been de~ c r i b e d ,5*3 ~ 7*566*56 7 and multiparame ter correlations of hydrolysis rate P. R. Byron, R. T. Guest, and R. E. Notari, J. Pharm. Sci. 70,1265 (1981). P. G . Ruifrok, Naunyn-Schmiedeberg’s Arch. Pharmacol. 319,185 (1982). 5 5 2 C. Treiner, C. Vaution, and G. N. Cave, J. Pharm. Pharmacol. 34,539 (1982). 5’3 S. Toon and M. Rowland, J. Pharm. Pharmacol. 32, Suppl., 8P (1980). ’54 B. Rittich and H. Dubsky, J. Chromatogr. 209,7 (1981). K. Valko and A. Lopata, J. Chromatogr. 252,77 (1982). ’56 U. Avico, E. Ciranni-Signoretti, and P. Zuccaro, Farmaco, Sci. Ed. 35, 590 (1980). 5 5 7 R. D. Budd, Clin. Toxicol. 17,375 (1980). ”* J. S. Millership and A. D. Woolfson, J. Pharm. Pharmacol. 30,483 (1978). J. S. Millership and A. D. Woolfson, J. Pharm. Pharmacol. 32,610 (1980). ’ 6 0 J. Bojarski and L. Ekiert, Chromatographin 15, 172 (1982). A. H. Stead, R. Gill, A. T. Evans, and A. C. Moffat, J. Chromatogr. 234,277 (1982). ”* J. Bojarski and L. Ekiert, J. Liq. Chromatogr. 6,73 (1983). 563 M. Sarsunowa and Z. Perina, Pharrnazie 32,476 (1977). 564 H. Nogami, T. Nagai, and H. Uchida, Chem. Pharrn. Bull. 17, 168 (1969). 5 6 5 H. Nogami, T. Nagai, and H. Uchida, Chem. Pharm. Bull. 17, 176 (1969). 5 6 6 S. Asada, M. Yamamoto, and Y. Hamada, Chem. Pharm. Bull. 27, 1663 (1979). ’~5’ A. I. Dyachkov, B. A. Ivin, 1. M. Vishnyakov, and E. G . Sochilin, Zh. Org. Khim. 11, 2182 (1975). ’O

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constants with "six number", 'T-NMR chemical shifts of (2-5, dissociation constants, and molecular connectivity indices have been e v a l ~ a t e d . ~ ~ ~ , ~ ~ ~ The Hammett-type correlation for the rate constants of 5-allyl-5-Rbarbiturates has been reported by Carstensen et al. and suggested for use in stability prediction^.^^' Similar correlations were also found for the hydrolysis of 5-arylidenebarbituric a ~ i d s . Linear ~ ~ ~free , ~energy ~ ~ relationships have also been reported for dissociation ~ o n s t a n f s , 4polarographic ~-~~ half-wave potentials,570fluores~ence~~ and luminescence phen~rnena,~' and 13C-NMR chemical shifts129for different classes of barbituric acid derivatives. Application of the dual substituent parameters method in LFER analysis of barbiturates, using Taft's polar and steric constants for various chemical and physicochemical properties, was also evaluated.571 The results of correlation analysis for barbituric acid derivatives should be interpreted carefully, bearing in mind that the majority of results deal only with compounds (sometimes a few) used in therapy, which restrict the full representation of the class. Although highly significant correlations are observed for closely related compounds, the generalization of such correlations often lowers their significance.Some problems can also be encountered with appropriate determination and/or selection of experimental data and parameters used in correlation analysis, but one can assume that this method will be further developed and will expand the range of its applicability, as indicated in more recent

VI. Closing Remarks Although the chemistry of barbiturates has been explored for a very long time, these compounds still attract the attention of chemists, as exemplified by a recently published synthesis for 157 as a potential cerebral perfusion agent for tomography574or by studies of the chemical and metabolic degradation of 158.575However, it is the medicinal application of barbiturate drugs and

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H. van der Veen, Ph.D. Thesis, State University of Leiden (1977). J. T. Carstensen, E. G. Serenson, and J. J. Vance, J . Pharm. Sci. 53,1547 (1964). 5 7 0 W. Welna and J. Bojarski, Pol. J . Chem. 52,987 (1978). 5 7 1 J. L. Mokrosz, Arch. Pharm. ( Weinheim, Ger.) 317,718 (1984). '72 S. Hada, S. Neya, and N. Funasaki, J. Med. Chem. 26,686 (1983). 5 7 3 S. C. Basak, C. Raychaudchury, A. B. Roy, and J. J. Gosh, Arzneim.-Forsch. 33,352 (1983). 5 7 4 P. C. Srivastava, A. P. Callahan, E. B. Cunningham, and F. F. Knapp, J . Med. Chem. 26,742 (1983). "'0.Lafont, C. Cave, B. Lambrey, J. P. Briffaux, C. Jacquod, and M. Miocque, Eur. J. Med. Chem. 18,163 (1983). 569

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associated chemical problems that are the main area of current research. For instance, pharmaceutical properties (stability) of solid forms of amobarbita1,576aminopyrine-barbital ~omplex,’~’and thiopental-y-cyclodextrin complexS78were studied recently in Japan. Studies on the adsorption of phenobarbital on activated charcoals79 and on the interaction between barbiturates and ethanols8’ are interesting from a toxicological point of view. Structural features of the barbiturate molecule which are required for its hypnotic, convulsant, and/or anticonvulsant properties have been summarized by Vida and Gerry,581 and numerous studies were devoted to physiological effects and pharmacological mechanisms of action of barbiturates in relation to chemical and stereochemical factors. Some recent articles and reviews are suggested on this fascinating and still incompletely elucidated subje~t.~”Clearly, the history of barbiturate? has many paragraphs yet to be written.

576

577

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A. Ikekawa and S . Hayakawa, Bull. Chem. Soc. Jpn. 55,3123 (1982). Y.Kawashima, S. Y.Lin, M. Ueda, and H. Takenaka, Drug Dev. Ind. Pharm. 9,285 (1983); Y. Kawashima, S. Y.Lin, M. Ueda, H. Takenaka and Y.Ando, J. Pharm. Sci. 72,514 (1983). K. Arimori, R. Iwaoku, M. Nakano, Y. Uemura, M. Otagiri, and K. Uekama, Yakugaku Zasshi 103, 553 (1983). K. A. Javaid and B. H. El-Mabrouk, J . Pharm. Sci. 72,82 (1983). A. H. Stead and A. C. Moffat, Hum.Toxicol. 2,5 (1983). J. A. Vida and E. H. Gerry, Med. Chem. 15, 151 (1977). J. A. Richter and J. R. Holtman, Prog. Neurobiol. 18,275 (1982); F. Leeb-Lundberg and R. W. Olsen, Mol. Pharmacol. 21, 320 (1982); P. R. Andrews and E. J. Lloyd, Med. Res. Rev. 2, 355 (1982); P. R.Andrews and L. C. Mark, Anesthesiology 57,314 (1982); R. J. Macdonald and M. J. McLean, Epilepsia 23, Suppl. 1, 7 (1982); G. A. R. Johnston and M. Willow, Trends Pharmacol. Sci. 3, 328 (1982); F. Leeb-Lundberg and R. W. Olsen, Mol. Pharmacol. 23, 315 (1983); S. H. Roth, K. S. Tan, and J. Tooth, Proc. West. Phnrmacol. Soc. 26,243 (1983); S. Toon and M. Rowland, J. Pharmacol. Exp. Ther. 225,752 (1983). J. W. Dundee and P. D. ,4. McIlroy, Anaesthesia 37,726 (1982).

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VII. Addendum This Section summarizes recent important publications that have appeared in the literature. Carroll et al. investigated solution conformations of barbiturates,584while studies on crystal structures of a variety of barbiturate H-bonded complexes indicated that the pharmacologically active barbiturates are more effective as donors than as acceptors in H - b ~ n d i n g . ~ ~ ~ Structure-activity relationship^,^^^ transport phenomena,587TLC separation on different reversed-phase chroma top late^,^^*-^ and chromatographic identification of 5,5-disubstituted barbiturates5” may be of interest for both medicinal and analytical chemists. Photostability of barbiturates in the solid state,591properties of isomeric N and 0 isopropyl derivatives of 2 (R = ethyl, R’ = ethyl or pheny1),592,s93enzymatic chlorination594 and gas phase synthesiss95of 1, and chromatographic resolution of enantiomers of some trisubstituted barbiturates have also been

ACKNOWLEDGMENT The authors are grateful to Professor Mitchell L. Borke for reading the manuscript and helpful comments.

584

F. I. Carroll, A. H. Lewin, E. E. Williams, J. A. Berdasco, and C. G. Moreland, J. Med. Chem. 27, 1191 (1984).

B. M. Craven, R. 0. Fox, and H.-P. Weber, Acta Crystallogr., Sect. B 38, 1942 (1982). P. R. Andrews, L. C. Mark, D. A. Winkler, and G. P. Jones, J. Med. Chem. 26, 1223 (1983). 587 S. A. Khalil, 0.Y.Abdallah, and M. M. Moustafa, Pharm. Acta Helu. 58, 307 (1983). 588 G. Grassini-Strazza and M. Crystalli, J. Chromatogr. 214,209 (1981). 589 T. Cserhati, B. Bordls, L. Ekiert, and J. Bojarski, J. Chromatogr. 287,385 (1984). s90 R. Dybowski and T. A. Gough, J. Chromatogr. Sci. 22,104 (1984). 5 9 1 J. Reisch and MM. Muller, Pharm. Acta Helu. 59, 56 (1984). 5 9 2 J. F. Mtnez, E. Gentric, J. Lauransan, and L. G. Bardou, Can. J. Spectrosc. 27,157 (1982). 593 J. F. Menez, M. Bourin, M. C. Colombel, C. Benamou, C. Larousse, and L. Bardou, Eur. J . Med. Chem.-Chim. Ther. 18,521 (1983). 594 M. C. R. Fransen and H. C. van der Plas, R e d . Trau. Chim. Pays-Bas 103,99 (1984). 595 D. J. Burinsky and R. Graham Cooks, Org. Mass Spectrom. 18,410 (1983). 596 G. Blaschke and H. Markgraf. Arch. Pharm. 317,455 (1984).

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ADVANCES IN HETEROCYCLIC CHEMISTRY. VOL. 38

Heterocyclic @-EnaminoEsters. Versatile Synthons in Heterocyclic Synthesis HEINRICH WAMHOFF lnstitut fur Organische Chemie und Biochemie der Universitiit Bonn. Bonn. Federal Republic of Germany

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . A . General Remarks . Reviews . . . . . . . . . . . . . . . . . . . B. The Concept of “Heterocyclic /?-Enamino Esters and Nitriles” . . . . . C . Heteroaromatic Enamino Esters (Nitriles). . . . . . . . . . . . . . I1. Synthetic Approaches . . . . . . . . . . . . . . . . . . . . . . A.GeneraI . . . . . . . . . . . . . . . . . . . . . . . . . B. Partially Saturated Heterocyclic /&Enamino Esters by Rearrangement Reactions C. Partially Saturated Heterocyclic /?-Enamino Esters by Direct Syntheses . . . D . Miscellaneous Syntheses. . . . . . . . . . . . . . . . . . . . E. Heteroaromatic /?-Enamino Esters . . . . . . . . . . . . . . . . 111. Structure and Spectral Properties . . . . . . . . . . . . . . . . . . A. Protonation . . . . . . . . . . . . . . . . . . . . . . . . B. Structures from UV, IR, and ‘H-NMR Data . . . . . . . . . . . . . C. ”C-NMR Data and Electron Distribution in the Enaminocarbonyl Chromophore . . . . . . . . . . . . . . . . . D. The Push-Pull Stabilization . . . . . . . . . . . . . . . . . . IV . General Considerations of Chemical Reactivity . . . . . . . . . . . . . V . Electrophilic Attacks on the 2-Amino Group (or the Carbon-3 Atom). Synthesis of Polynuclear Heterocyclic Systems. . . . . . . . . . . . . . . . . . A . With Isocyanates, Isothiocyanates, and Sulfenyl Chlorides . . . . . . . . B. Reactions with Imido Esters, 0-Alkyllactim Ethers, Formamide, and Formaldehyde . . . . . . . . . . . . . . . . . . . . . . . C. Heterocondensed 1,3-Oxazinones from 2-Acylamino Derivatives and Dihalotriphenylphosphoranes. . . . . . . . . . . . . . . . . . D . Heterocondensed [1,2-u]Pyrimidines . . . . . . . . . . . . . . . E. Electrophilic Addition to Carbon-3 . . . . . . . . . . . . . . . . F. Miscellaneous Reactions. . . . . . . . . . . . . . . . . . . . VI. Nucleophilic Attacks of Amines and Diamines . . . . . . . . . . . . . VII. Cycloadditions and Reactions with Acetylenic Esters . . . . . . . . . . . VIII. 2-(Triphenylphosphorylidenamino) Esters.The Cycloaddition-Ring Enlargement Sequence . . . . . . . . . . . . . . . . . . . . . A. Formation and Properties . . . . . . . . . . . . . . . . . . . B. Polar Cycloaddition-Ring-EnlargementReactions with Acetylenic Esters . . C . Subsequent Reactions . . . . . . . . . . . . . . . . . . . . D . Miscellaneous Reactions Employing Phosphorus Compounds . . . . . . IX . Photochemistry . . . . . . . . . . . . . . . . . . . . . . . . ~

299

300 300 301 301 301 301 302 302 304 305 309 309 310 311 315 316 318 318 324 330 333 337 339 343 347 351 351 352 354 355 355

.

Copyright 01985 by Academic Press Inc. All rights of reproduction in any form reserved. ISBN 0-12-020638-2

300

HEINRICH WAMHOFF

[Sec. 1.A

X. Heterocyclic /I-Enamino Nitriles . . . . . . . . . . . . . . . . . . 357 A. Syntheses. . . . . . . . . . . . . . . . . . . . . . . . . 357 B. Properties and Comparison with Enamino Esters . . . . . . . . . . . 360 C. Heterocyclization Reactions . . . . . . . . . . . . . . . . . . 360 D. Dimroth Rearrangements to Thieno- and Furo[2,3-d]pyrimidophanes . . . 363 E. Miscellaneous Reactions of Heteroaromatic P-Enarnino Nitriles . . . . . . 365 XI. Conclusion and Outlook. . . . . . . . . . . . . . . . . . . . . 367

I. Introduction A. GENERAL REMARKS. REVIEWS Many condensed heterocyclic systems, especially when linked to a pyrimidine ring, play an important role in biologically active compounds, e.g., as potential medicinal agents,’ in the plant protection areala, and in cancer and virus research.lb This article illustrates the rather versatile role of a certain class of compounds, which are ideally suited for the purpose of serving as multifunctional building units for new and promising compounds in one or two easy reaction steps. Although in the last decade the chemistry and wide applicability of enamines in organic synthesis’ have been intensively studied and belong to the classical arsenal of preparative organic chemistry, little attention has been paid to the special class of heterocyclic fi-enamino esters and nitriles. An exception is a survey on heterocyclic enamines.j There also exists one comprehensive review of heterocyclic fi-enamino esters4 and another approach on annelation of a pyrimidine ring to an existing ring.5

* R. K. Robins, P. C. Srinivasta, G. R. Revankar, T. Novinson, and J. P. Miller, Lect. Heterocycl. Chem. 6, 93 (1982); H. Rapoport, ibid. 4,47 (1978); W. J. Irwin and D. G. Wibberley, Adu. Heterocycl. Chem. 10, 149, esp. 197 (1969). l a K. H. Buchel, ed., “Chemistry of Pesticides.” Wiley (Interscience), New York, 1983. IbH. E. Skipper, R. K. Robins, J. R. Thomson, C. C. Cheng, R. W. Brockman, and F. M. Schmahl, Jr., Cancer Res. 17,579 (1957) [ C A 52,4850(1958)]; A. D. Broom, I. L. Shim, and G. L. Anderson, J. Org. Chem. 41,1095 (1976); E. Hayashi et al., Yakugaku Zasshi98,1560(1978) [CA 90, 15alllh (1979)l; J. Ashby and B. M. Elliott, in “Comprehensive Heterocyclic Chemistry” (A. R. Katritzky and C. W. Rees, eds.), Vol. 1, p. 1 1 1. Pergamon, Oxford, 1984; J. K. Landquist, ibid, p. 144. * A. G. Cook, “Enamines, Synthesis, Structure, and Reactions.” Dekker, New York, 1969; M. E. Kuehne, Synthesis, 510 (1970); S. Hunig and H. Hoch, Fortschr. Chem. Forsch. 14,235 (1970); S. F. Dyke, “Chemistry of Enamines.” Cambridge Univ. Press, London and New York 1973; P. W. Hickmott, Tetrahedron 38, 1975,3363 (1982). K. Blaha and 0. Cervinka, Adu. Org. Chem. 4,1(1963). H. Wamhoff, Lect. Heterocycl. Chem. 5,61(1980). A. Albert, Adu. Heterocycl. Chem. 32, 1 (1982).

Sec. II.A]

30 1

HETEROCYCLIC p-ENAMINO ESTERS

B. THECONCEPT OF “HETEROCYCLIC /?-ENAMINO ESTERS AND NITRILES” If an enaminocarbonyl or enaminonitrile moiety exists as part of a partially saturated heterocyclic ring system, it is called a “heterocyclic/?-enaminoester” or “nitrile,” to acknowledge that these cyclic variants possess an enamino double bond located between an ester or nitrile group and an adjacent heteroatom (see Scheme 1). This concept covers a great deal of a rather heterogenous number of different heterocycles, but all have the common structural feature and are closely related to both enaminocarbonyl and enaminonitrile compounds and to heterocycles.

C. HETEROAROMATIC ENAMINO ESTERS(NITRILES) If the heterocyclic nucleus is fully aromatic, the compounds are called “heteroaromatic enamino esters” and “nitriles” (see Scheme 2). Because of the aromatic ring there might be a modified electronicsituation with respect to the enaminocarbonyl chromophore (cf. Section 111). R

R

11. Synthetic Approaches A. GENERAL While most classical enamines and open-chain enamino esters2 are obtained by condensation, e.g., of a secondary amine with a keto compound, heterocyclic/?-enaminoesters can be obtained only by special reactions as, e.g., rearrangement or direct syntheses. Some of these are depicted in this section.

302

HEINRICH WAMHOFF

[Sec. 1I.C

B. PARTIALLY SATURATED HETEROCYCLIC P-ENAMINO ESTERS BY REARRANGEMENT REACTIONS Heterocyclic p-enamino esters which are dihydrofurans,6 dihydro4Hpyrans,6 and dihydro-4H-thiopyrans' are easily accessible in a special case of the so-called "acyl lactone rearrangement."' Starting from the appropriate M cyano-y- and d-lactones and thiolactones (6),catalytic amounts of alkoxide ions lead to ring cleavage, rearrangement, and ring closure of the terminal Xgroup with the cyano group (7, Scheme 3). Owing to the ring cleavage mechanism of styrene oxide-via rearrangement of the intermediary M cyanolactone-a 4-phenyl-substituted 2-amino furan-3-carboxylic ester ( 9 )is obtained, as shown by 'H-NMR.9Jo

SCHEME3

C. PARTIALLY SATURATED HETEROCYCLIC p-ENAMINO ESTERS BY DIRECT SYNTHESES While oxiranes afford with sodium ethylcyanoacetate only a-cyano-ybutyrolactone, i.e., the insertion of the hydroxyethyl moiety into ethyl cyanoacetate,6 thiiranes give with sodium cyanoacetate, in a one-step S. E. Glickman and A. C. Cope, J. Am. Chem. SOC.67,1012 (1945);F. Korte and K. Trautner,

Chem. Ber. 9 5 2 8 1,295 (1962);P. L. Pacini and R. G. Ghirardelli, J. Org. Chem. 31,4133 (1966).

' F. Korte and H. Wamhoff, Chem. Eer. 97, 1970 (1964).

* F. Korte and K. H. Biichel, Angew. Chem. 71,709 (1959); in "Newer Methods of Preparative Organic Chemistry" (W. Foerst, ed.), Vol. 3, p. 199. Academic Press, New York, 1964; H. Wamhof and F. Korte, Synthesis, 151 (1972). E. Dradi and V. Vecchietti, Chim. Ind. (Milan) 53, 1040 (1971) [ C A 76, 59336m (1972)l; for more examples, cf. Campaigne et a[.'" l o E. Campaigne, R. L. Ellis, M. Bradford, and J. Ho, J . Med. Chem. 12, 339 (1969).

Sec. II.C]

HETEROCYCLIC

303

P-EN AMINO ESTERS

procedure, ethyl 2-amino-4,5-dihydrothiophene-3-carboxylate (10) and some polymeric side products." This simple procedure can be also transferred to 1tosylaziridine, which is cleaved by sodium alkyl cyanooacetates to give 2amino-1-tosyl-A2-pyrroline-3-carboxylates (11)' (Scheme 4).

CO,R

I v Na' N J ) - : T H

I

Tos

CN

Tos

R = CH,, C2Hs

(11)

SCHEME 4

Ethyl 2-amino-1,4,5,6-tetrahydropyridine-3-carboxylate (13) is obtained under mild conditions by mutual treatment of 3-carbethoxy-2-piperidinone (12) with triethyloxonium tetrafluoroborate and then ammonia. l 3 The synthesis of p-enamino esters such as 2-amino-l-aryl-3-carbethoxypyrrolin-4one (15) possessing a carbonyl function in the partially saturated ring is (14) with accomplished by cyclization of ethyl y-chloro-a-cyano-acetoacetate arylamines.14 As 'H-NMR spectra show, 15 exists predominantly in the pdicarbonylenamine form (Scheme 5). Furthermore, furanones of the general

SCHEME 5

H. R. Snyder and W. Alexander, J. Am. Chem. SOC.70,217 (1948). J. Lehmann and H. Wamhoff, Synthesis, 546 (1973). l 3 H. Wamhoff and L. Lichtenthaler, Synthesis, 426 (1975). l4 K. J. Boosen, Helu. Chim. Acta 60,1256 (1977). I'

304

[Sec. 1I.D

HEINRICH WAMHOFF

type 17 are accessible by base-catalyzed cyclocondensation of ethyl 4chloroacetoacetate (16) with isocyanates'5 (Scheme 6). CH,CI

I c=o I CHCONHR' I

-

CHzCI

I I ,OH C= 1 "HR*

c=o

COZCZH,

C0ZCZH5

SCHEME 6

D. MISCELLANEOUS SYNTHESES Extending the Hantzsch synthesis and in the course of producing new 4aryl-l,4-dihydropyridines related to the powerful calcium antagonist Nifedipine (Adalat),16 arylalkylideneacetoacetates, ketones, and malonic esters (18 and 21) have been treated with ketenaminals (19) to give 2-amino1,4-dihydropyridine-3-carboxylic esters 20 and 22" (Scheme 7). This reaction was also applied to 4-arylalkylidene-2-methyl-1,3-oxazolinone-5.'*

R'

l:fizR

lcozR -

R2*H+

-H~O

0

HzN

NHz

N H

NH2

SCHEME 7 " L. Capuano and

W. Fischer, Chem. Ber. 109,212 (1976). Cf. review: F. Bossert, H. Meyer, and E. Wehinger, Angew. Chem. 93, 755 (1981); Anyew. Chem., Int. Ed. EngL 20,762 (1981). l 7 H. Meyer, F. Bossert, and H. Horstmann, Liebigs Ann. Chem., 1895 (1977). H. Meyer, F. Bossert, and H. Horstmann, Liebigs Ann. Chem., 1483 (1978).

l6

Sec. II.E]

HETEROCYCLIC /?-ENAMINO ESTERS

305

In the presence of piperidine, compound 18, and ethyl cyanoacetate, ethyl 2amino-4H-pyran-3-carboxylates(23) are formed.” In a similar way, tlbenzoylcinnamonitriles (24) react with ethyl cyanoacetate to achieve ethyl 2amino-4H-pyrane-3-carboxylates (25)20(Scheme 8).

SCHEME8

E. HETEROAROMATIC /?-ENAMINO ESTERS Numerous heteroaromatic b-enamino esters are given with appropriate references in Schemes 9 and 10.2’-52Of the numerous preparative approaches to heteroaromatic fl-enamino esters, only two very general routes are briefly discussed. Bayer AG, Ger. Offen. 2,235,406 (1974)(inventors: H. Meyer, F. Bossert, W. Vater, and K. Stoepel) [CA 80,120765 (1974)l. I 0 M.Quinteiro, C. Seoane, and J. L. Soto, Tetrahhedron Lett., 1835 (1977);J . Heterocycl. Chem. 15,57 (1978);M. R. H. Elmoghayer, M. A. E.Khalifa. M. K. A. Ibraheim, and M. H. Elnagdi, Monatsh. Chem. 113,53 (1982). K. Gewald, Chem. Ber. 98,3571 (1965). 2 2 K. Gewald and A. Martin, J. Prakt. Chem. 323,843 (1981). 2 3 K. Gewald, M. Kleinert, B. Thiele, and M. Hentschel, J . Prakt. Chem. 314,303 (1972). 24 H. Wamhoff and B. Wehling, Synthesis, 51 (1976). I 5 F. Langer, F. Wessely, W. Specht, and P. Klezl, Monatsh. Chern. 89,239 (1958);J. Derkosch and 1. Specht, ibid. 92, 542 (1961). I 6 K. Gewald, E. Schinke, and H. Bottcher, Chem. Ber. 99,94 (1966);K. Gewald, ibid., 1002. ” C. A. Grob and 0. Weissbach, Helu. Chim. Acta 44,1748 (1961). H. Kano, Y.Makisumi, and K. Ogata, Chem. Pharm. Bull. 6,105 (1958);[ C A 53,7140 (1959)l. A. Dornow and H. Teckenburg, Chem. Ber. 93,1103 (1960);F. Korte and K. Storiko, ibid. 94, 1956 (1961);G. Desimoni and P. Griinanger, Gazz. Chim. Ital. 97,25 (1967). 30 J. Goerdeler and H. Horn,Chem. Ber. 96, 1551 (1963). 3 1 P. Schmidt and J. Druey, Helu. Chim. Acta 39,986 (1956).

306

[Sec. 1I.E

HEINRICH WAMHOFF

(28)' '

(27)"

(29)"

(31)25

C0,Et

COzEt a

N

H

(32)26

HQN"z

,

(33)27 SCHEME 9

H. Dorn, G. Hilgetag, and A. Zubeck, Chem. Ber. 98, (1968);C. C. Cheng, J.Heterocycl. Chem. 5, 195 (1968); R. K. Robins, J . Am. Chem. Soc. 78,784 (1956). 33 H. Wamhoff and A. Atta, unpublished. 34 J. Goerdeler and G. Gnad, Chem. Ber. 99, 1618 (1966). 35 0.Dimroth, Ber. Dtsch. Chem. Ges. 35,4059 (1902); Justus Liebigs Ann. Chem. 364,203 (1908). 36 H.Wamhoff, S.-Y. Yang, and J. Bohlen, unpublished. 37 H. H. Fox, J. Org. Chem. 17,547 (1952). j * H. Wamhoff, unpublished results; W. F. Keir, A. H. MacLennan, and C. S. H. Wood, J.C.S. Perkin I , 1002 (1978). 39 R. Grewe, Hoppe-Seyler's 2. Physiol. Chem. 242,89 (1936). 40 J. L. Bernier, A. Lefebvre, J. P. Henichat, R. Houssin, and C. Lespagnol, Bull. Soc. Chim. Fr., 32

616(1976).

K. Gewald, J . Prakt. Chem. 31,205 (1966). G. V . Boyd, J. Chem. SOC.,C , 3873 (1971). 43 K. H. Bauer, Ber. Dtsch. Chem. Ges. 71,2226 (1938). 44 K. Gewald and J. Schael, J . Prakt. Chem. 315,39 (1973). R. Matusch and K. Hartke, Chem. Ber. 105,2594 (1972). 46 G. B. Bennett, R. B. Mason, and M. J. Shapiro, J. Org. Chem. 43,4383 (1978). 47 K. Gewald and H. J. Jansch, J . Prakt. Chem. 318,313 (1976). K. Gewald and G . Heinhold, Monaish. Chem. 107, 1413 (1976). 49 K. Gewald, P. Bellmann, and H. J. Jansch, Z. Chem. 15, 18 (1975); K. Gewald and P. Bellmann, Liebigs Ann. Chem., 1534 (1 979). 5 0 K. Saito, S. Kambe, A. Sakurai, and H. Midorikawa, Synthesis, 1056 (1982). 5 1 L. C. Cheney and J. R. Piening, J. Am. Chem. Soc. 67,729 (1945);0.Hromatka, D. Binder, and K. Eichinger, Monatsh. Chem. 104, 1513 (1973). 5 z K. Gewald, P. Bellmann, and H. J. Jansch, Liebigs Ann. Chem., 1623 (1980). 41

Sec. II.E]

307

HETEROCYCLICj-ENAMINO ESTERS

R' = H, NH2

H

(PhCI)

R' = CH,, Ph, ClPh

(42)"

(43Y9

(45)4'

(47)43

CH, (48)44

W 4 0

(49)4'

SCHEME 9 (Continued)

308

[Sec. 1I.E

HEINRICH WAMHOFF

R R

Me

R (51)47

(52)48

(53)49

C02R (SS)5

’

(56)52

SCHEME10. Some “reverse” heteroaromatic enamino esters.

2-Aminofuran-, -pyrrole-, and -thiophene-3-carboxylatesand -3-nitriles such as 58 are obtained in a simple, one-step reaction from a-0x0-alcohols, -amines, and -thiols (57) with methylene-active nit rile^.^^ Thus ethyl 2-amino4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (59) results from cyclohexanone, sulfur, and ethyl ~ y a n o a c e t a t e ’ ~(Scheme ’~~ 1 1). The accessible

a Z = O;Y=CN b Z=NH;Y=CN,CO,R c Z = S; Y = CN, CO,R, CONH,, COR

SCHEME 11

53

K. Gewald, Chimia 34, 101 (1980); Lect. Heterocycl. Chem. 6, 121 (1981), and references cited therein.

Sec. III.A]

HETEROCYCLIC b-ENAMINO ESTERS

309

alkoxymethylenecyanoacetates (60)54are smoothly cyclized with hydroxylamine, hydrazine, and their substituted analogues to afford five-membered heteroaromatic 8-enamino esters (61)29,55(Scheme 12). This review mainly covers partially saturated heterocyclic p-enamino esters; but some heteroaromatic 8-enamino esters are also discussed. H)+co’R RO

H) j ~ ~ c o z R

HX-NHR,

CN

NH,

R = alkyl, aryl;

X

= 0, NH

SCHEME 12

111. Structure and Spectral Properties Heterocyclic /?-enamino esters differ in many respects from enamines,’ open-chain 8-enamino esters,’ and heterocyclic enamines,’ all of which point to a specific electron distribution in their enaminocarbonyl chromophore. In the following,particular attention is paid to spectroscopicstudies of these title compounds and to the consequences for their structures, protonation behavior, tautomerism, stability, and mesomeric forms.

A. PROTONATION Consistent with previous I R investigations (in CDC13/TFA),6*7‘H-NMR spectroscopy shows that protonation of heterocyclic 8-enamino esters, such as 62, occurs exclusively at C-3 (“Cg-protonation”)to give oximmonium and thiaimmonium salts 6355”(Scheme13). In these ‘H-NMR spectra, HX(cf. 63) couples with the neighboring methylene protons to display a characteristic triplet signal; depending on ring size and heteroatom X; 6 = 4.20-4.62 (J = 7.0-9.0 Hz). However, furan- and thiopheneenamino esters (64) are protonated at C-5 to form 2,5-dihydro heterocycles (65).26*56 R. G. Jones, J . Am. Chem. Soc. 73, 3684 (1951); 74, 4889 (1952); Roche Products Ltd., U.S. Patent 2,375,185 (1945) (inventors: F. Bergel, A. Cohen, and J. W.Haworth) [CA 39, 3307 (1945)]. ” A. Michaelis and E. Remy, Ber. Dtsch. Chem. Ges. 40,1020 (1907); C. C. Cheng and R. K. Robins, J. Org. Chem. 21, 1240 (1956). 5 5 s H. Wamhoff, Tetrahedron 26,3849 (1970). “C. T. Wie, S. Sunder, and C. DeWitt Blanton, Jr., Tetrahedron Lett., 4605 (1968). 54

310

[Sec. 1II.B

HEINRICH WAMHOFF

,

CO R(C N)

CO,R(CN)

NHZ

B. STRUCTURES FROM UV, IR, AND ‘H-NMR DATA The bathochromic shifted, intense UV maxima of the partially saturated 270-297.5 nm; log E = 4.07-4.28) confirm heterocyclic p-enamino esters (A, a considerable z-electron delocalization ( p-A-overlap) in the enaminocarbony1 chr~mophore,~’ which can be depicted by dipolar mesomeric canonical formulae 66a-66e possessing a high transition moment5’ (Scheme 14). A strong participation of the ring heteroatom can be discerned.

SCHEME 14

’’ N. H. Cromwell and W. R. Watson, J. Org. Chem. 14,411 (1949). H. WamholT, H. W. Diirbeck, and P. Sohar, Tetrahedron 27, 5873 (1971); about the conformation, cf. E. Dradi and G. Gatti, Org. Med. Reson. 3,479 (1971).

Sec. III.C]

311

HETEROCYCLIC /3-ENAMINO ESTERS

This resonance involving dipolar canonical formulas is unambiguously supported by a significant positive solvatochromism as shown by the wavelength dependence of the UV absorptions in different solvents with increasing dielectric constants (Table I).” In the IR spectra,’* characteristic absorption is found in the regions 3500-3000 and 1750-1500 cm-’. The position and shape of the vNH2vibrations (v, and vas) point to free rather than chelated (to the neighboring ester carbonyl) amino groups. In the region of the enaminocarbonyl bands (1700- 1500 cm- ’), three characteristic, strong bands are found. Deuterium exchange experiments indicate that these bands belong to absorptions of group frequencies. Thus following Dabrowski6’ who investigated open-chain enamino esters, these absorptions have been named “enamino-ester bands EI, EII, and EIII” (i.e.,coupled vibrations of vc=o, vex, and dNH2bands). For detailed descriptions of the IR spectra see references 12, 13, and 58. Because of the participation of the enamine double bond in the resonance of the aromatic ring of heteroaromatic p-enamino esters, the group frequency character of the individual bands is low. Thus the EI band is essentially vc=o. Similarly, p-enamino nitriles do not exhibit coupled vibrations since the nitrile absorption does not parti~ipate.’~.~’ The ‘H-NMR spectra indicate that these potentially tautomeric compounds exist exclusively in the enamine form 67a (Scheme 15). The amine protons are found as broad resonance signals in the region 6 5.25-6.85 and are similar to conjugated primary amines. From these values, an intramolecular hydrogen bridge (cf. 67c) to the neighboring ester carbonyl can be excluded; all data are given in references 12, 13, and 58.

P?‘‘.. -:

0 flc’OR

+

H

O

4 -

_./

SCHEME 15

c. I3C-NMR DATAAND ELECTRON DISTRIBUTION IN THE ENAMINOCARBONYL CHROMOPHORE The 13C-NMR spectra support the results of the other spectroscopic investigations described above. In addition, this method allows direct H. Wamhoff and E. Gierke, unpublished results. J. Dabrowski, Spectrochim. Actn 19,475 (1963). 61 H. Wamhoff and H. A. Thiemig, Chem. Ber. 118 (1985), in press.

s9 6o

TABLE I POSITIVE SOLVATOCHROMISM' Solvents ( E ) Isooctane

H3C

HI C f i c ~ ~ 2 H H3C

CH3CN (37.5)

DMSO

(37.6)

(48.9)

CH30H (33.6)

265 (3.69)

269 (4.18)

269 (4.17)

270 (4.15)

272 (4.19)

273 (4.20)

274 (4.1 7)

265

(3.95)

269 (4.23)

269 (4.17)

270 (4.27)

272 (4.19)

273 (4.33)

274 (4.50)

265 (3.82)

268 (4.12)

269 (4.05)

272 (4.12)

271 (4.07)

272 (4.25)

274 (4.23)

266 (4.13)

269 (4.19)

268 (4.22)

270 (4.21)

212 (4.32)

212 (4.30)

274 (4.18)

0 C02C2H5 NH

H3C

THF (7.4)

DMF

(1.9)

0

For each absorbance maximum, given in nm,the logarithm of the molar absorptivity is included in parentheses.

HCONH2 (109.5)

Sec. III.C]

313

HETEROCYCLIC /9-ENAMINO ESTERS TABLE I1

'3C-NMR DATA OF ETHYL2 - A ~ N O - 4 , ~ - D I H u D R O ~ m r R A N - 3 - C A R B O X Y L6%-d A~ (SEE SCHEME16)"

Compound

c-2

68a

68c

168.11s 167.W 167.60s

73.64s 73.61s 80.63s

68d

166.10s

72.70s

Compound

c-7

68b

68a

68b 68c

58.71t 58.80t 57.96t

68d

58.20t

(144.0)

c-3

c-4

C-5

C-6

27.50t 40.94t 37.08d (135.6) 34.10t

70.70t 87.53 82.28d (143.0) 70.1Od

168.11s 169.06s 168.26s

C-8

c-9

c-10

14.909 14.90t 14.39q (126.4) 14.609

28.32q 14.39q (126.4) 21.509

28.32q 13.76q (126.4) -

167.40s

'Solvent, CDCI,; TMS as internal standard; the coupling constant J (in Hz) is given in parentheses. measurements of the electron density of the individual carbon atoms, and gives the electron distribution in the enaminocarbonyl chromophore. In Table I1 13C-NMR data are given for a number of 4,5-dihydrofurans (Scheme 16).62Schemes 17 and 18 present more 13C-NMR data of additional heterocyclic /?-enamino esters, which are, however, limited to unsaturated atoms C-2 and C-3.63 All of the enamino esters 68a-d, 69-72 show the common feature of a strongly electron deficient (2-2, as in an amidine-C or a ketene-S, N-(-O,N-)aminal,6' while C-3 does not appear as an olefinic carbon

SCHEME 16

63

H. Wamhoff and G. Haffmanns, unpublished results. H. WamhotT and L. Lichtenthaler, Chem. Ber. 111,2813(1978); H. Wamhoff and G. Hendrikx, ibid. (in press).

3 14

[Sec. 1II.C

HEINRICH WAMHOFF Structure

c-2

c-3

159.28

72.05

154.50

80.43

155.63

90.66

163.33

92.12

H

I

Tos

,C02C2 H

64

~~

SCHEME17. "C-NMR data of C-2 and C-3 for 69-72.

atom but instead as a highly shielded trigonal carbon atom, owing to the electron-donating effects of the heteroatoms.66Thus as a consequence, these "C-NMR values point to a high degree of polarization in the enamine double bond, as shown in the canonical formula 66b-e. These I3C-NMR values agree with the reported data of methyl and ethyl P-aminocrotonate.66aEven for anthranilic esters, characteristic polarization of the aromatic ring for C- 1 and C-2 can be observed66b(see Scheme 18).As a consequence, the electron density H. Wamhoff and J. Nagelschmitz, unpublished results. R. L. Smith, D. W. Cochran, P. Cund, and E. J. Cragoe, Jr., J . Am. Chem. SOC.101, 191 (1979); C. Skotsch and E. Breitmaier, Chem. Ber. 113,795 (1980). 66 The I3C NMR values of the OH-form of 3-methyl-5-pyrazolone point to a similar electron distribution; (in DMSO): C-3 140.1, C-4 89.2, C-5 161.6 ppm; E. Breitmaier, unpublished. Sadtler Standard Carbon-13 Spectra, No. 2331 and 2647. Sadtler Research Laboratories, Philadelphia, Pennsylvania, In "Bruker (2-13 Data Bank," Vol. 1. Bruker-Physik, Karlsruhe.

64

6s Cf.

Sec. III.D]

HETEROCYCLIC /?-ENAMINO ESTERS

c - 2 160.00 (2-3: 83.60

C-2: 160.70 C-3 83.30

C-1: 150.60 c - 2 110.00

C-1: 150.80 c-2: 110.10

315

SCHEME 18. ‘,C-NMR data of C-1, C-2, and C-3.

at the 2-NH2 group is quite low, and therefore the nucleophilicity of the nitrogen atom is rather weak. Thus many typical reactions for enamines cannot be expected.

D. THEPUSH-PULL STABILIZATION From the spectroscopic data of Sections II,A-C it can be concluded that partially saturated heterocyclic p-enamino esters possess a specific push-pull stabilization owing to the conjugation of electron-donating amino group and electron-withdrawingester f~nction.~’ Push-pull stabilization is responsible for the remarkable stability of this class of compounds; similar stabilization allows isolation of certain antiaromatic cyclobutadienes or nonaromatic oquinodimethanes.682-Aminofurans, -pyrroles, and -thiophenes, because of their extremely large electron density, are generally unstable and sensitive

SCHEME19 Sadtler Standard Carbon-13 Spectra, No. 150. Sadtler Research Laboratories, Philadelphia, Pennsylvania, In L. F. Johnson and W.C. Jankowski, “Carbon-13 NMR Spectra,” No. 296. Wiley (Interscience),New York, 1972. Push-pull alkenes: Cf. H. Kristen and K. Peseke, Wiss. Z. Wilhelm-Pieck-Unio. Rostock, Math.-Naturwiss. Reihe 25, 1123 (1976) [ C A 88, 1055187m (1978)J Cf. R. Gompper, Bull. SOC.Chim. Belg. 92,781 (1983), and references cited therein.

66b

‘’

316

HEINRICH WAMHOFF

[Sec. IV

toward many reagent^;^' and most classical synthetic approaches to them have failed. 2-Amino-4,5-dihydrofurans and -thiophenes (74)have not yet been isolated in spite of many attempts, e.g., by cyclization of 4-hydroxy- and 4-mercaptobutyronitriles (73).In all cases, only the 2-imino hydrochloride 75 was i ~ o l a t e d ’(Scheme ~ 19). However, a novel synthesis of 5-amino-2,3- or 5-imino-2,5-dihydrofurans 78B from 4-hydroxy-4,4-dialkylbut-2-yne nitriles 76A and primary amines has been reported”’; but in agreement with the resonance formulas shown for 76B,these compounds might be considered to be once again (internally) pushpull stabilized, like the furanones 17.’’

SCHEME19a

IV. General Considerations of Chemical Reactivity Based on the spectroscopic information presented in Sections 111,A-D, some general reaction pathways can be deduced for the partially saturated heterocyclic /?-enamino esters. Electrophiles are expected to attack at the electron-rich position 3 (cf. 77).If the attacking agent possesses an additional (terminal) nucleophilic group or one is formed during the reaction, then ring closure may take place at the electron-deficient C-2 (cf. 78).The electrophile is also capable of attacking the 2-amino group (79),which exhibits weak nucleophilic behavior, but reacts with electrophiles of high electron defi69

’O

’On

A. P. Dunlop and F. N. Peters, “The Furanes,” p. 183ff. Van Nostrand: Reinhold, Princeton, New Jersey, 1950; F. F. Blicke, in “Heterocyclic Compounds”(R. C. Elderfield, ed.), Vol. 1, p. 228. Wiley, New York, 1950; S. Gronowitz, Adu. Heterocycl. Chem. 1, 1 (1963). K. S. Topchiev and M. L. Kirmalova, Dokl. Akad. Nauk SSSR 63,281 (1948) [CA 43,2579 (1949)l;H. Nohira, Y. Nishikawa,Y. Furuya, and T. Mukaiyama, Bull. Chem. Soc. Jpn. 38,897 (1965) [ C A 63, 7012 (1965)l; American Cyanamid Co., U.S. Patent 3,223,585 (1965) inventor: W. Addor) [ C A 63,7012 (1965)J Z. T. Fomum, P. F. Asobo, S.R. Landor, P. D. Landor, J . Chem. Soc., Chem. Commun.,p. 1455 (1983).

Sec. IV]

HETEROCYCLIC b-ENAMINO ESTERS

317

ciency, e.g., heterocumulenes (Scheme 20). A terminal nucleophilic group present from the beginning or formed during the reaction might now attack the ester function (cf. 80). In both cases, condensed heterocyclic systems are formed (78,80).

SCHEME 20

Nucleophiles can attack competitively both the 3-ester group (81) and the electron-poor C-2 (82); in the latter case, subsequent ring-cleavage reactions (83)or other elimination processes (84)might occur in order to regenerate the enaminocarbonyl moiety in a thermodynamically downhill process (Scheme 21). When the enaminocarbonyl group is part of an aromatic ring, as

CEReoR Nu

SCHEME 21

318

HEINRICH WAMHOFF

[Sec. V.A

in heteroaromatic p-enamino esters 85, reactivity comparisons should be made with anthranilic esters 86 and related compounds (Scheme 22).

SCHEME 22

V. Electrophilic Attacks on the 2-Amino Group (or the Carbon-3 Atom). Synthesis of Polynuclear Heterocyclic Systems A. WITHISOCYANATES, ISOTHIOCYANATES, AND SULFENYL CHLORIDES One of the most versatile transformations with subsequent heterocyclization is the smooth and mostly exothermic addition of electron-poor isocyanates to the 2-amino function of almost all types of heterocyclic enamino esters (cf. 87). A mixed urea (88) is first formed; it can be easily isolated but in most cases is cyclized in situ with aqueous base to afford heterocondensed uracils (89) in high yields” (Scheme 23). This reaction

SCHEME 23

pathway is based on a very early communication of Behrend et ~ 1 . ’ This ~ method has been used to obtain highly substituted furo[2,3-d] pyrimidines, ”

’’

H. Wamhoff, Chem. Ber. 101, 3377 (1968); Thieno[2,3-d]pyrimidines: F. Sauter and W. Deinhammer, Monatsh. Chem. 104, 1593 (1973). R. Behrend, F. C. Meyer, and Y. Buckholz, Justus Liebigs Ann. Chem. 314,200 (1901).

Sec. V.A]

HETEROCYCLIC /?-ENAMINO ESTERS

319

SCHEME 24

e.g., 90 (Scheme 24) as potential antimalarials." Reactive aryl i~ocyanates'~ give urea 88 in an exothermic reaction; but for more electron-rich, less reactive alkyl isocyanates, the reaction mixture must be warmed in order to complete addition. Scheme 25 depicts the rather broad applicability (Formulas 91107).'"80 The caffeine and isocaffeine isomers derived from 103 show diuretic and cardiac activitie~.'~ Isothiocyanates normally act as weaker electrophiles and need more drastic conditions to give the thioxo derivative^;^^ also organic bases, such as pyridine, have been successfully employed76 for the cyclization step, so that this heterocyclization procedure may be carried out as a one-pot, threecomponent (enamino ester, isocyanate, organic base) reaction. Higher carbamoylated products, such as 109, are smoothly hydrolyzed in aqueous 5% KOH to the pyrido[2,3-d]pyrimidines 11076(Scheme 26). After chlorolysis of furo[2,3-d]pyrimidines (11 1) with phosphorus oxychloride, 5-(2-~hloroethyl)uracils(112) are obtained. These can be transformed to thieno[2,3-d]pyrimidines (113) or rearranged with triethylamine to give novel 4-chlorofuro[2,3-d] pyrimidines (114), which are useful starting materials for novel tetracyclic systems (cf. 115) via photolysis of the 4-azido derivative*' (Scheme 27).

Cf. S. Petersen, in"Methoden der Organischen Chemie" (Houben, Weyl, Muller, eds.), 4th ed., p. 192ff. Thieme, Stuttgart, 1952; R. G. Arnold, J. A. Nelson, and J. J. Verbane, Chem. Rev. 57, 50 (1957). 74 H. Wamhoff and B. Wehling, Chem. Ber. 109,2983 (1976). " H. Wamhoff, unpublished results. 76 H. Wamhoff and L. Lichtenthaler, Chem. Ber. 111,2297 (1978). 7 7 J. Goerdeler and H. Horn, Chem. Ber. 96,1551 (1963). P. Schmidt, K. Eichenberger, and J. Druey, Helu. Chim. Acta 41, 1052 (1958); P. Schmidt, K. Eichenberger, M. Wilhelm, and J. Druey, ibid. 42,349 (1959). 79 H. Wamhoff, S.-Y. Yang, and J. Bohlen, unpublished. J. Lehmann and H. Wamhoff, Chem. Ber. 106,3533 (1973). H. Wamhoff and C. von Waldow, Chem. Ber. 107,2265 (1974); 110,1730 (1977). 73

320

[Sec. V.A

HEINRICH WAMHOFF

(91)” X = 0 (92)” x = s (93)14X = NR

(103)”

(94)” (95)”

x =0 x =s

(%)16

X = NH

(97)’’ X = Y = CH (98)’’ X = N Y=CH (99)” X = CH Y=N

(10S)fJO

(104y9

0

$1

H

H

SCHEME25

Sec. V.A]

HETEROCYCLIC/?-ENAMINO ESTERS

SCHEME 26

SCHEME 21

321

322

[Sec. V.A

HEINRICH WAMHOFF

Among the many new condensed systems, many of potential biological interest, pyrroI0[2,3-d]pyrimidines*~ deserve special attention as aglycones of antibiotic and cytostatic principles, such as Tubericidine, Toyocamycine, and Sangivamy~ine.~~ Treatment of suitably substituted pyrrole- and pyrrolinenamino esters (I16 and 118) with isocyanates represents a new and versatile approach to this interesting class of compounds (117, 119)74 (Scheme 28). Treatment of the enamino nitrile 120 with methyl isocyanate

[

,

EtO~CINLCO~Et (;C

dN-’ ’ KOH

NHCONHBz]

NHBz CONHBz

N H

H NAO

SCHEME 28

under more energetic conditions leads to the triscarbamoyl derivative 121, which is cyclized in turn in sodium methoxide to afford pyrrolo[1,2-a]-1,3,5Me

H

N [CONHMe],

I

Me

SCHEME 29

83

V. Amarnath and R. Madhav, Synthesis, 837 (1974). G. Acs and E. Reich, in “Antibiotics” (P. Gottlieb and P. D. Shaw, eds.), Vol. 1, p. 494ff. Springer-Verlag, Berlin and New York, 1967.

Sec. V.A]

HETEROCYCLIC b-ENAMINO ESTERS

323

triazine (122) in the first preparati~n’~ of the ring system of the antibiotic Viomycine8* (Scheme 29). It is noteworthy that ethyl 2-aminoindole-3carboxylate (33)27does not show any readiness to add isocyanates to give the

benzo[b]pyrro10[2,3-d]pyrimidines.~~ In a related reaction, isopropylsulfamoyl chloride (123) reacts with the enamino esters 32 and 38 to give the sulfonyl analogues of ureas, e.g., 124. Basic ring closure leads then to a benzo[b] thieno[3,4-e]-2,1,3-thiadiazine 2,2dioxide (125) and a pyrazolo[3,4-e]-2,1,3-thiadiazine 2,2-dioxide (126), respectivelye6 (Scheme 30). Similarly, chlorosulfonyl isocyanate (127)87 affords with several enamino esters (after saponification and ring closure HNCHMe,

32+

c1’

I so,

-QTJco2Et NSO,NHCHMe, H

H

SCHEME 30

J. R. Dyer, C. K. Kellogg, R. F. Nassar, and W. E. Streetman, Tetrahedron Lett., 585 (1965). H. Wamhoff and B. Wehling, Chem. Ber. 108,2107 (1975). 86 H. Wamhoff and M. Ertas, Synthesis, p. 190 (1985). ” R. Graf, Chem. Ber. 89,1071 (1956); Angew. Chem. 80,179 (1968); Angew. Chem., Znt. Ed. Engl. 7, 172 (1968); J. K. Rasmussen and A. Hassner, Chem. Reo. 76,389 (1976). 84

*5

324

HEINRICH WAMHOFF

[Sec. V.B

of the intermediate ureas 128) heterocondensed and unsubstituted uracils 129-13la6(Scheme 31). 0

SCHEME 31

B. REACTIONS W I T H IMIDO ESTERS, 0-ALKYLLACTIM ETHERS, FORMAMIDE, AND FORMALDEHYDE Imido esters, lactim ethers, and formamide are less reactive than isocyanates and isothiocyanates. Thus a higher temperature must be used. When the desired compounds are sufficiently thermostable, condensed products can be obtained via 132 and 133 in high yields (Scheme 32). Thus with imido esters, the bicyclic 4-pyrimidinones 134,and with lactim ethers, tricyclic systems 135 are smoothly formed in high yield.’ This heterocyclization method has been employed in many syntheses (see Scheme 33).89-93

H. Wamhoff, Chem. Ber. 102,2739(1969). H. Wamhoff and B. Wehling, Chem. Ber. 108,2107(1975). H. Wamhoff, Chem. Ber. 105,743(1972). ” S. Rajappa, B. G. Advani, and R. Sreenivasan, Indian J . Chem., Sect. B 14B,391 (1976)[ C A 85, 89

19265111(1976)l. 92

‘3

V. I. Shvedov, I. A. Kharizomenova, and A. N . Grinev, Khim. Gelerosikl. Soedin., 765 (1975) [ C A 83,164119k (1975)J M.S. Manhas and S. G. Amin, J . Heterocycl. Chem. 13,903(1976).

Sec. V.B]

HETEROCYCLIC 8-ENAMINO ESTERS

325

L

SCHEME 32

A special modification of this heterocyclization is the treatment of pyrimidinenamino esters (151)with lactam acetals such as 15294;153 is the primary condensation product, and basic ring closure affords the tricycle 154 (Scheme 34). Formamide is a powerful C-N-heterocyclization reagent. 2-Formamidino derivatives are intermediates. Robins transformed 3-aminopyrazole-4carboxamide to a 4-oxopyrazolo[3,4-d]pyrimidine (155)” by heating in formamide. In boiling formamide, 155 was obtained from ethyl 3aminopyrazole-4-carboxylate(38y1(Scheme 35). From the enamino ester 59 and formamide a 5,6,7,8-tetrahydrobenzo[b] thieno[2,3-d ]pyrimidin-4-one (156) was ~ b t a i n e d , ’ ~as well as the aromatic thionaphtheno[2,3-d]pyrimidine (157).97This heterocyclization method shows broad applicability V. G. Granik, N. B. Marchenko, and R. G . Glushkov, Khim. Geterosikl. Soedin., 1549 (1978) [CA 90,121529~ (1979)l;E. 0.Sochneva, N. P. Solov’eva, and V. G. Granik, ibid., 1671 [CA 90, 12153Oq (1979)l. 9 5 R. K. Robins, J . Am. Chem. Soc. 78,784(1956). 96 V. I. Shvedov, V. K. Ryzhkova, and A. N. Grinev, Khim. Geterosikl. Soedin., 459 (1967)[CA 68, 5951911 (1968)l. 97 K. Gewald and G . Neumann, Chem. Ber. 101,1933(1968). 94

3 26

[Sec. V.B

HEINRICH WAMHOFF

SCHEME33. Heterocyclization with Starting Material

Product

13

H

13

(137)76

13

0 37

RqJJTph H

(139)''

31

33

(141)n9

Sec. V.B]

HETEROCYCLICfl-ENAMINO ESTERS

irnido esters and lactarn ethers Product

Starting Material

41

41

42

43

36

36

32

'

& f i H J nN'

N'

(143)"'

321

328

[Sec. V.B

HEINRICH WAMHOFF

OH I

SCHEME 34

SCHEME 35

both for partially saturated and aromatic enamino esters, as shown in Scheme 36.98-'02 Compound 156 was independently obtained from 2-amino4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamideand formic acid.' O3

'*

W.Ried and R. Giesse, Justus Liebigs Ann. Chem. 713,149 (1968). K.Gewald and 0.Calderon, Monatsh. Chem. 108,611 (1977). loo W.Ried and R. Giesse, Justus Liebigs Ann. Chem. 713,143(1968);V. P.Arya and S. P. Ghate, 99

Indian J. Chem. 9,1209 (1971)[ C A 76,99604d(1972)J R.G. Glushkov, V.A. Volokova, and 0.Yu.Magidson, Khim.-Farm. Zh. 1,25(1967)[CA 68, 105,143f (1968)J K.Gewald and H. J. Jansch, J. Prakt. Chem. 315,779 (1973). l o 3 F. Sauter, Monatsh. Chem. 99,1507(1968);101,535(1970).

Sec. V.B]

329

HETEROCYCLIC 8-ENAMINO ESTERS

0

I

0

0

(158)98.99

(159)"'

Ph

0

(160)'''

R

0

H (161)"'

0

0

(164)"'

(165)"

(166)''Z

(167)49

SCHEME 36

Some partially saturated and heteroaromatic p-enamino esters, such as 8

(X = S , n = 2), 32, and 36, with formaldehyde and acetaldehyde give the methylenediamines 168-170 by N-methylene linkage lo4(Scheme 37). Double head-to-tail condensation of the pyrazolenamino ester 37 leads to a symmetrical tetrazocane (171); a 3:3-adduct (172) was detectedlo4 as a side product. From the IR and 'H-NMR data, it follows that 168-170 display a chelate bridge from the 2-amino group to the adjacent 3-ester function, owing to the electron-donating influence of the N-alkyl grouplo4(Scheme 38). lo4

H. Warnhorn, G . Hendrikx, and M. Ertas, Liebigs Ann. Chem., 489 (1982).

330

[Sec. V.C

HEINRICH WAMHOFF

QTJCO2"

COZEt

NH-CH,-NHR

EtOzCl

NH-CH,-NH

,CH3

I

o

z

c

a C O z E t

s,N'

S

~

~

~

E t 0 2 C ~

NH-CH-NH I

SCHEME 37 H

N-N

N-N

NH

H

(171) C0,Et

SCHEME

38

c. HETEROCONDENSED 1,3-OXAZINONES FROM 2-ACYLAMINO

DERIVATIVES AND DIHALOTRIPHENYLPHOSPHORANES

Dihalogentriphenylphosphoranes(X,PPh,) formed in situ from triphenyldibromotetrachloroethane,106 and a phosphanes, hexachl~roethane,'~~ base"' are powerful reagents for heterocyclic synthesis.'08 By treatment of lo'

lo'

R. Appel, Angew. Chem. 87,863(1975);Angew. Chem., Int. Ed. Engl. 14,801(1975);R. Appel and M. Halstenberg, in "Organophosphorus Reagents in Organic Synthesis"(J.1.G. Cadogan, ed.), p. 387ff.Academic Press, London, 1979. G. Bringmann and S. Schneider, Synthesis, 139 (1983). Standard base: triethylamine"'; in some cases improved yields with 1,5-diazabicyclo[4.3.0]5-nonene (H. WamholT, A. Bohle, and R. Liittgens, unpublished results). E. g.. L. Farkas, J. Keuler, and H. Wamhoff, Chem. Ber. 113,2566(1980).

Sec. V.C]

HETEROCYCLIC fl-ENAMINO ESTERS

33 1

the N-acylated S-heterocyclic8-enamino esters 8 (X = S,n = 1,2) and 32 with dihalogentriphenylphosphoranes, heterocondensed 1,3-oxazinones 173 and 174are formed smoothly.10gThis facile ring closure (instead of dehydration to ketenimineslo5) is explained either by rapid and preferred attack of an intermediate imide chloride (175)on the neighboring ester group or by chlorolysis of the 3-ester moiety 176'" and subsequent cyclization (Scheme 39). Bisacylenaminoesters, such as 27 or 178,are cyclized in a similar way to give bis-1,3-oxazinones 177 and 179104*109 (Scheme 40).By means of P4Sl0, oxazinones 173 and 174 are smoothly converted to the novel, deep-red 1,3-thiazin-6-thiones 180 and 181,which are in turn selectively photooxidized with singlet-oxygen,via spiro-1,2,3-dioxathietanes(182),to afford 1,3-thiazin6-ones 183l" (Scheme 41). 0

0

(173)

N=C

NHCOR

(175)

(176)

SCHEME39

With hydrazine, 180 affords 184 and in a subsequent elimination, 4hydrazinobenzoCb]thieno[2,3-d]pyrimidine (185),which can be smoothly cyclized with the orthoester R(OEt), in a known procedure"2 to form a 1,2,4triazolo[4,3-c] benzo[b]thieno[3,2-e]pyrimidine Upon heating with D. Achakzi, M. Ertas, R. Appel, and H. Wamhoff, Chem. Ber. 114,3188 (1981). D. J. Burton and W. M. Koppes, J. Org. Chem. 40,3026 (1975). H. Wamhoff and M. Ertas, Angew. Chem. 94,800 (1982); Angew. Chem., Int. Ed. Engl. 21,794 (1982); S.Leistner and G. Wagner, 2. Chem. 17,95 (1977). l L 2D. J. Brown and K. Shinozuka, Aust. J. Chem. 33,1147 (1980); C . J. Shoshoo, M. B. Devani, G . V. Ullas, S. Ananthan, and V. S. Bhadti, J. Heterocycl. Chem. 18,43 (1981). H. Wamhoff and M. Ertas, Chem.-Ztg. 107,344 (1983).

log

332

[Sec. V.C

HEINRICH WAMHOFF

XzPPh3

NH-CO-Y-CO-NH

SCHEME 40

S

WLR 0

Sec. V.D]

333

HETEROCYCLIC /3-ENAMINO ESTERS

N-dichloromethylenesulfonamide (186a), 5-aminopyrazole-4-carboxylicacid (38, Et = H) is converted to a pyrazolo[3,4-d][1,3]oxazine ( W b ) . ' lJa NHNH,

38

+ CI,C=NSO,R

0

I

Ph

I

SOZR

SCHEME 42

D. HETEROCONDENSED [ 1,24]]PYRIMIDINES N-Heterocyclic /3-enamino esters which are unsubstituted in the 1-position are well suited for a double condensation reaction when treated with 1,3dicarbonyl compounds to give annelation of a [1,Zalpyrimidine ring. Thus, the condensation of 2-aminopyrroline affords pyrrolo[ 1,2-a]pyrimidines.***'l 4 Shvedov et al. treated 2-amino-3-pyrrolecarbonitrile187 with /3-diketones or ethyl acetoa~etate'~."~ to give 188. No ring closure '13'

l4

F. L. Merchan, Synthesis, 965 (1981). A. Le Berre and C. Renault, Bull. SOC.Chim. Fr., 3139 (1969). V. I. Shvedov, I. A. Kharizomenova, L. B. Altrukhova, and A. N. Grinev, Khim. Geterosikl. Soedin., 428 (1970)[ C A 73,25403(1970)l.

3 34

[Sec. V.D

HEINRICH WAMHOFF

RL= CO,R, CN R2 = CH,, C02R

(189)

SCHEME 43

SCHEME 44

X

= OH,

NH,

Sec. V.D]

335

HETEROCYCLIC 8-ENAMINO ESTERS

involving the 3-ester group to form 189 is ob~erved’~ (Scheme 43). In a similar way, ethyl 2-aminoindole-3-carboxylate33 affords, with several 1,3-dicarbony1 compounds, pyrimido [1,2-a] indoles 190; again no pyrido [2,3-b] indole 191 could be detecteda9 (Scheme 44). Accordingly, ethyl cyanoacetate gives the expected tricyclic amino derivative 192, but now with a reverse regiospecifi~ity.~~ COa I Et 13+CH,

I

-

o ( ; E t

COlEt

0U

I

O

I

I

I

198

SCHEME 45

336

[Sec. V.D

HEINRICH WAMHOFF

Similarly, by treatment with malonic ester, 2-amino- 1,4,5,6-tetrahydropyridine-3-carboxylate (13) is smoothly and exclusively converted to the pyrido[ 1,2-a]pyrimidine system 193.' l6 Basic catalysts convert asymmetrical 1,3-dicarbonyl compounds, such as acetoacetates 194 and cycloalkanone2-carboxylates, to pyrido[1,2-a]pyrimidines 195 and 197a; isomers such as 198 were not found.'16 Structures 195 and 197a are supported by their UV spectra.' 'H-NMR spectroscopy of 195 reveals a tautomeric equilibrium (1951 # 19511)' " (Scheme 46). "J

'*

a C 0 2 E t

0U

R

-

oco2Et

0U

R

R=Me,Ph

SCHEME 46

In line with the above, 13 affords with diethyl oxalate the imidazo[1,2alpyrimidine 196' l6 (Scheme 47). However, ethyl 2-amino-3-quinoline-

SCHEME 47

carboxylate (47) with ethyl rnalonate yields-similar to the Dornow and Neuse cyclizati~n"~-the potentially tautomeric benzo[b]-1,8naphthyridine 197bB0(Scheme 48). 3,5-Diamino-4-ethoxycarbonylpyrazole

'I9

H. WamhofT and L. Lichtenthaler, Chem. Ber. 111,2813 (1978). C . F. H. Allen, H. R. Beilfuss, D. M. Burness, G . A. Reynolds, J. F. Tinker, and .I. A. Van Allan, J. Org. Chem. 24,779 (1959). H. L. Yale and E. R. Spitmiller, J. Heterocycl. Chem. 13,797 (1976). A. Dornow and E. Neuse, Arch. Pharm. Ber. Dtsch. Pharm. Ges. 288, 174 (1955).

Sec. V.E] .

337

HETEROCYCLIC /l-ENAMINO ESTERS

,H...

B

0

II

(197b)

SCHEME 48

(37) reacts with fl-bifunctional reagents to form pyrazolo[ 1,5-a]pyrimidines 198 and 199 (Scheme 49).120

37 (198)

H3C U

C

H

,

SCHEME 49

E.

ELECTROPHILIC ADDITION TO CARBON-3

The highly electron-deficient 1,2,4-triazoline-3,5-diones 200’ 2 1 ~ 1 2 2readily attack the 3-position of ethyl 2-amino-4,5-dihydrofuran-3-carboxylates (8, X = 0,n = 1) at room temperature to give the imino lactone adducts ‘’O

’”

E. M. Kandeel, V. B. Baghos, 1. S. Mohareb, and M. H. Elnagdi, Arch. Pharm. Ber. Dtsch. Pharm. Ges. 316,713 (1983). H. Wamhoff and K. M. Wald, Org. Prep. Proced. Int. 7,251 (1975); cf. M. Fieser and L. F. Fieser, “Reagents for Organic Synthesis,” Vol. 6, p. 75ff.Wiley (Interscience), New York 1977. H. Wamhoff and G . Kunz, Angew. Chem. 93,832 (1981);Angew. Chem., Int. Ed. Engl. 20,797 (1981), and references cited therein; H. Wamhoff and G. Kunz, unpublished results.

338

[Sec. V.E

HEINRICH WAMHOFF

201'23 Saponification, methylation, and heating in DMSO/NaC1'24 afford rearrangement to the spiro lactones 202'23 (See Scheme 50). However, direct treatment of lactone 203 with DMSO/NaCl leads under elimination of HNCO to phenylureidobutenolides204.lz3 CO,Et

I

I (X = 0, n = 1)

Ph

//

(201)

0

SCHEME 50

In tetrahydrofuran the dihydrofurans 8 (X = 0, n = 1) react with maleic anhydride at room temperature to yield pyrano[4,3-c]pyridines 205 via a complex addition-rearrangement scheme' 2 5 involving betaine 206 (Scheme 51). Furthermore, in the formation of the naphthyridines 207 and 208 from 13 and acetylenic esters or methyl acrylate, the first step consists of a Michaeltype attack on the electron-rich C-3'I6 (Scheme 52). H.Wamhofl and K. Wald, Chem. Ber. 110,1716 (1977). S . Takei and Y.Kawano, Tetrahedron Lett., 4389 (1975); cf. also A. P. Krapcho, Synthesis, 805, 893 (1982), and references cited therein. G. Szilagyi and H.Wamhoff, Synthesis, 698 (1980).

Sec. V.F]

HETEROCYCLIC B-ENAMINO ESTERS

R

339

5A0-

Et0,C

H

SCHEME 51

SCHEME 52

F. MISCELLANEOUS REACTIONS Recently, some work has appeared which deals with reactions of heterocyclic fl-enamino esters with bifunctional reaction partners leading in two or more consecutive steps to polycyclic heterocyclic systems. Thus, ally1 isothiocyanate

340

[Sec. V.F

HEINRICH WAMHOFF

gives with thiophene 32 after attack of the 2-amino group in a double cyclization reaction, a benzo[b] thieno[2,3-d] thiazolo[3,2-~]pyrimidine (209)lZ6(Scheme 53). 1,2-Tri- and -tetramethylenethieno[2,3-d]pyrimidin-4-

0

SCHEME 53

ones 211 are formed by heating of 32 with 3- and 4-chloroalkyl nitriles 2IO1” (Scheme 54). 0

SCHEME 54

1,3-Thiazolenamino esters 212 give thiazolo[3,2-a]thiazolo[5,4-d]pyrimidine systems such as 215 2 8 via several steps involving intermediates 213 and 214 (Scheme 55). H. K. Gakhar, A. Madan, A. Khanna, and M. Kumar, J . lndian Chem. SOC.55,705 (1978)CCA 9 0 , 6 3 4 6 ~(1979)l. 12’ V. A. Kovtunenko, L. V. Soloshonok, A. K. Tyltin, and F. S. Babichev, Ukr. Khim. Zh. (Russ. Ed.) 49,855 (1983) [CA 99, 175 709 j(1983)l. 128 P. B. Talukdar, S. K. Sengupta, and A. K. Datta, lhdian J . Chem., Sect. B 22B,243 (1983) [ C A 99, 122 4OOv (1983)l. 126

Sec. V.F]

34 1

HETEROCYCLIC /3-ENAMINOESTERS 0

0

1

R2 = H R2 = CSNHR3

0

SCHEME 55

342

HEINRICH WAMHOFF

[Sec. V.F

2-Amino-N-cyanomethyl-3-thiophenecarboxamide (216),easy accessible according to the Gewald method,” cyclizes in the presence of sodium methoxide to give 2-amino-3,4-dihydrothieno[2,3-f]-1,4-diazepine-5-one (217),which is converted with acetylhydrazine to a thieno[3,2-f] [1,2,4]triazolo[4,3-a] [ 1,4]diazepine-6-one (218).lZ9These compounds are of interest because of their hypnogenic and anxiolytic properties f Scheme 56). By a one-step procedure, 2-aminothiophene-3-carboxylates 219 are transformed with cyclohexanone by heating with HMPT and catalytic amounts of PPA to 4-dimethylamino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quinolines such as 220.’30 TetrazoloC1,5-c] thieno[3,2-c]pyrimidines (222) are obtained from the thiophenenamino esters 32 and nitriles, via the thienopyrimidinones, the

(221) X = OH x = CI X = NHNH,

SCHEME58 I3O

K. H. Weber and H. Daniel, Liebigs Ann. Chem., 328 (1979). A. Osbirk and E. B. Pedersen, ACIUChem. Scand, Ser. B B33,313 (1979).

Sec. VI]

343

HETEROCYCLIC fi-ENAMINO ESTERS

4-chloro derivatives, and by diazotization of the 4-hydrazino derivatives 22113' (Scheme 57). In a series of consecutive steps involving 224 and 225 the new polyheterocyclic ring system 226 has been made from 223132(Scheme 58). NHeteroaromatic enamino esters, such as 227, and ethoxymethylene cyanoacetate condense to afford the vinylenamino ester 228;with hydrazines a 3aminopyrimidine is annelated (229)'32a (Scheme 59).

0

SCHEME 59

VI. Nucleaphilic Attacks of Amines and Diamines Reaction of alkanediamines 230 with ethyl 2-amino-4,5-dihydro-3furancarboxylates (8: X = 0,n = 1) does not give furo[2,3-e]-1,4-diazepine5-ones 231.'33*'34 In stead, as high-resolution I3C-NMR spectra show, in a sequence of addition and elimination steps (232-233), 3-(2imidazolidiny1idene)- and 3-(hexahydro-2-pyrimidinylidene)dihydro-2-(3H)furanones 234 are formed'35 (Scheme 60). The constitutions of 234 were confirmed by 13C-NMR gated d e c o ~ p l i n g . ' ~ ~ C. J. Shishoo, M. B. Devani, M. B. Karvekar, G. V. Ullas, G. V. Ananthan, V. S. Bhadti, R. B. Patel, and T. P. Gandhi, Indian J. Chem., Sect. B 21B, 666 (1982)[ C A 97,198154~(1982)l. I. Lalezari and M. H. Jabari Sahbari, J . Heterocycl. Chem. 15,873(1978). J. Y.Merour, J. Heterocycl. Chem. 19,1425 (1982). 133 P. L. Pacini and R. G. Ghirardelli, J . Org. Chem. 31,4133(1966). H. Wamhoff and C. Materne, Justus Liebigs Ann. Chem. 754, 113 (1971);H. Wamhoff, C. Materne, and F. Knoll, Chem. Ber. 105,753 (1972);H. Wamhoff and C. Materne, ibid. 107, 1784 (1974). Z. T. Huang and H. Wamhoff, Chem. Ber. 117,622(1984). ''I

'''

344

HEINRICH WAMHOFF

[Sec. VI

SCHEME 60

Methylamine reacts with 8 (X = 0;n = 1) to afford a mixture (40:60) of E,Z-235l3 5 (Scheme 61). Similarly, o-phenylenediamine, l$-diaminonaph,NHCH,

(E-235)

(2-235) SCHEME 61

thalene, 2-aminophenol, and 2-aminoethanol lead, after ring cleavage and subsequent lactonization, to a-(2-benzimidazolyl)- (236), ce(2-perimidinyl)(237),a-(2-benzoxazolyl)- (238),and a-(2-oxazolin-2-yl)-y-lactones(239)124 (Scheme 62). Thus reaction of dinucleophiles with 8 (X = 0, n = 1) provides a simple and excellent access to a-heterocyclic substituted y-lactones.

Sec. VI]

HETEROCYCLIC B-ENAMINO ESTERS

(240)

C02Me I

us

-

-cn30n

SCHEME 63

R

345

346

[Sec. VI

HEINRICH WAMHOFF

Furthermore, it has been shown that compounds of type 235 are versatile starting materials for addition and cyclization reactions employing reactive triple and double bonds. With methyl propiolate, syn addition takes place to afford the adducts 240. In the presence of alcohols, compounds 240 are cyclized to give the imidazo[1,2-~]pyridines and pyrido[ 1,Za]pyrimidines 241'36 (Scheme 63). By treatment with methyl acrylate, the lactone derivatives 235 give the spiro compounds 242 in an addition and cyclocondensation sequence.' 37 With dimethyl acetylenedicarboxylate, 235 forms several condensed and unsaturated spiro compounds 243, similar to 242,' 37 as well as the tricyclic b-lactone 244 (Scheme 64). 0

MeO$

us

R

SCHEME 64

Furthermore, the dihydrofurans 8 (X = 0, n = 1) condense with fivemembered heterocyclic amidine derivatives via elimination of ethanol to R

SCHEME 65 2. T. Huang and H. Wamhoff, Chem. Ber. 117,1856 (1984).

''' 2. T. Huang and H. Wamhoff, Chem. Ber. 117,1926 (1984).

0

Sec. VII]

HETEROCYCLIC 8-ENAMINO ESTERS

347

afford the azolopyrimidines 245 and 246138,’39 (Scheme 65). In some cases, subsequent heterocyclization steps may be easily added. Compounds 244 and 248, obtained with 2-amino-s-triazole and 2-aminobenzimidazole (247), produce, on heating in a mixture of acetic and sulfuric acids, the novel fur0 [2,3: 5’,6]- 1,2,4-triazolo[1,5-a]pyrimidine (249) and fur0 [2,3: 2’,3’]benzoimidazo[ 1,2-a] pyrimidine (250) (Scheme 66). R

(247)

I SCHEME 66

VII. Cycloadditions and Reactions with Acetylenic Esters Although cycloadditions to enamines are well known,’ the partially saturated heterocyclic /?-enamino esters, as, e.g., 8, display only a very weak tendency toward cycloaddition reactions, and Diels-Alder-type (4+ 2) cycloadditions have not yet been observed. From the 1,3-dipoles known today,140 170 hr of treatment of the enamino esters 8 (X = 0, n = 1) with

13’

13’

I4O

M. H. Elnagdi and H. Wamhoff, Chem. Lett., 419 (1981). M. H. Elnagdi and H. Wamhoff, J . Heterocycl. Chem. 18,1287 (1981). R. Huisgen, Angew. Chem. 75,604,742 (1963);80 329 (1968);Angew. Chem., Int. Ed. Engl. 2, 565, 633 (1963); 7, 321 (1968); J . Org. Chem. 33, 2291 (1968); R. A. Firestone, ibid. 33, 2285 (1968);C. Grundmann, Fortschr. Chem. Forsch. 7,62 (1966);A. Padwa, Angew. Chem. 88,131 (1976);Angew. Chem., Int. Ed. Engl. 15, 123 (1976).

348

HEINRICH WAMHOFF

[Sec. VII

phenylazide leads-similar to the reaction of 2,3-dihydrofuran 14' presumably to a cycloadduct 251,which is stabilized by an eliminating ring cleavage to give 5-amino-4-(2-ethoxycarbonyloxyalkyl)-1-phenyl-1,2,3triazole 252142(Scheme 67). Benzphenylhydrazide chloride 253,the precursor

-N A +piG+

sf

N//

Ph

I

Ph

SCHEME 67

of diphenylt~itrilimine,'~~ reacts with 8 (X = 0, n = 1) by acylation of the 2amino group (254);rearrangement involving C-2 then gives a-(s-triazoly1)-ylactones 25514* (Scheme 68). Treatment of 8 (X = 0,n = 1) with methyl

Ph SCHEME 68

R. Huisgen, L. Mobius, and G. Szeimies, Chem. Ber. 98, 1138 (1965). H. Wamhofi' and P. Sohiir, Chem. Ber. 104,3510 (1971). 143 R. Huisgen, M. Seidel, G. Wallbillich, and H. Knupfer, Tetrahedron 17,3 (1962); H. Wamhoff and M. Zahran, unpublished results. 14'

142

Sec. VII]

349

HETEROCYCLIC B-ENAMINO ESTERS

propiolate and dimethyl acetylenedi~arboxylate'~~ illustrates the different paths available for the primary adduct 256. Polar cycloaddition affords (via ring enlargement of the nonisolable condensed cyclobutene 257) C0,Me

8

I 111

(X = 0 , n = 1) + c

CO2Et ..:... CH=C-C0,Me

-d

0, - - - -.NH2 '

(Z-259)

+

%

(E-259)

efJo Cbo HiEt 'COzMe

OR H

H

C02Et O

N\

C=CHCO,Me / C0,Me

SCHEME 69 144

H. Wamhoff and J. Hartlapp, Chem. Ber. 109, 1270 (1976).

(257)

350

[Sec. VII

HEINRICH WAMHOFF

6,7-dihydroazepines 258. The Z and E adducts E,Z-259 react in different ways: either to form the furo[2,3-b]pyridoles 259 and 260145or, after expulsion of isocyanic acid, vinylcyclopropanes 261144(Scheme 69). By this method the interesting ring system in fur0[2,3-b]pyridines'~~is constructed, for the first time starting from the furan moiety. Dimethyl acetylenedicarboxylate adds also to the 2-amino group to afford imino lactone 262.'44 Upon acid-catalyzed hydrolysis, the furo[2,3-b]pyridine 259 is cleaved to 263, which in turn cyclizes either to another furo[3,2-c]pyridine (264)or to a pyrano[4,3-c]pyridine (265)'44 (Scheme 70). Better results in the ring enlargement reaction leading to 258 are obtained with the corresponding 2(triphenylphosphoranylidenamino)esters (cf. Section VIII).

259

!Ao

EtOZC 0

H

SCHEME 70

The adducts of heteroaromatic fl-enamino esters with dimethyl acetylenedicarboxylates 266 are cyclized in a base-catalyzed reaction to yield 4-0x0-1,4-dihydro-2,3-pyridinedicarboxylicderivatives 26714' (Scheme 7 1). Ethyl 2-amino-3-thiophenecarboxylate(26)2' also gives, with dimethyl acetylenedicarboxylate, a wide variety of cyclization products (268-271, E = C02Me)'48 (Scheme 72). 14'

E. Spinner and G. B. Yeoh, Tetrahedron Lett., 5691 (1968); J . Chem. SOC.8,279 (1971).

146

J. R. Stevens, R. H. Beutel, and E. Chamberlin, J. Am. Chem. SOC.64,1093 (1942); E. Ritchie, Aust. J . Chem. 9,244 (1956).

14'

H. Biere and W. Seelen, Liebigs Ann. Chem., 1972 (1976). H. Biere, C. Herrmann, and G. A. Hoyer, Chem. Ber. 111,770(1978).

"*

Sec. VIII.A]

HETEROCYCLIC B-ENAMINO ESTERS

35 1

SCHEME 71

E

E

E

SCHEME 72

VIII. 2-(Triphenylphosphorylidenamino)Esters. The Cycloaddition-Ring Enlargement Sequence

A. FORMATION AND PROPERTIES Heterocyclic /?-enaminoesters of type 8 (X = 0,S; n = 1,2) with dihalotriphenylphosphoraneslo’ afford the resonance-stabilized iminophosphoranes 272 and 273 in high yields’49 (Scheme 73). As supported by spectroscopic data, the iminophosphorane group participates in the pushpull resonance of the electron distribution depicted in Section II1,C and in

14’

H.Wamhoff, G. Haffmanns, and H. Schmidt, Chem. Ber. 116,1691 (1983).

352

[Sec. VII1.B

HEINRICH WAMHOFF

n = 1) (273)

(272)

SCHEME 13

canonical forms 272/273 1-111 (Scheme 74).Alkyl iodides alkylate at the place with the highest electron density, i.e., at C-3, giving the phosphonium iodide 274. Compound 274 is smoothly converted by aqueous alkali to 2-imino lactones 27514' (Scheme 73).

I

I1

111

R = COzR,CN SCHEME 14

B. POLARCYCLOADDITION-RINGENLARGEMENT REACTIONS WITH ACETYLENIC ESTERS Unlike the unsubstituted enamino esters 8, the iminophosphorane group in 272/273 can be considered as a protecting group with a latent functionality. Thus methyl propiolate and dialkyl acetylenedicarboxylates now give high yields of the polar cycloaddition products. An independent and detailed report concerning this cycloaddition-ring enlargement sequence will be published e l s e ~ h e r e ' ~here ~ ; only the general principles and some of the primary results are discussed. H. Wamhoff, in preparation.

Sec. VIII.B]

HETEROCYCLIC 8-ENAMINO ESTERS

353

Under mild reaction conditions, the intermediate cyclobutene adducts 276 undergo in situ a CJ + II ring-enlargement reaction (277)owing to the strong polarizing effect of both push (2-iminophosphorane group) and pull (3-ester function) groups. In a simple, one-step procedure, insertion of the acetylenic moiety takes place with 5 + 7 transformation in ring size and, in the case of the six-membered thiopyrane 278 novel types of thiocines (279)are smoothly obtainedI4' (Scheme 75). This transformation has been achieved also by other RO,C

&R

N=PPh,C0,Me N=PPh,

E-E-E

N=PPh,

N=PPh,

SCHEME 75

g r o ~ p s ' 52 ~ ~with ~ ' heterocyclic enamines and enamino lactones. However, in the case of the 2-(triphenylphosphoranylideneamino)esters and nitriles (278), derived from 32 and X,PPh,, stable ylides (280)have been obtained, most likely via adducts 279ls3(Scheme 76). r

R = CN, C0,Et

1

SCHEME76

D. N. Reinhoudt and C. G. Kouwenhoven, Tetrahedron Lett., 5203 (1972); Rec. 7 h u . Chim. Pays-Bas92,865(1973);93,129(1974);D. N. Reinhoudt and C. G.Leliveld, Tetrahedron Lett., 3119(1972). 152 D. J. Haywood and S. T. Reid, J.C.S. Perkin I , 2457 (1977). l S 3 H. Wamhoff and G . Haffmanns, Chem. Ber. 117,585 (1984).

3 54

[Sec. VII1.C

HEINRICH WAMHOFF

C. SUBSEQUENT REACTIONS After the ring-enlargement reaction has been accomplished, the iminophosphorane group can be employed in a subsequent step; with phenyl isocyanate, resonance-stabilized carbodiimides (281) are obtained, which proved to be versatile starting materials for many heterocyclization reactions leading to novel 6:7, 6:8, and 5:6:7 combinations of heterocondensed pyrimidines (282)’” (Scheme 77). RO,C H+ __t

ElOH

N=C=N-Ph

H

SCHEME I1

Ph

0

0

II

+ (MeNH),POPh H

-

e N-CH

3

Sec. 1x1

HETEROCYCLIC B-ENAMINO ESTERS

355

D. MISCELLANEOUS REACTIONS EMPLOYING PHOSPHORUS COMPOUNDS A multistep preparation of a thieno[3,2-e]-1,4-diazepin-2(3H)-one (285) has been accomplished, starting from the thienooxazinone 284 obtained from methyl 3-acetylaminothiophene-3-carboxylate (283) and phosphorus pentachloride.’ 54 Similarly, 3-methylthieno[2,3-d]pyrimidin-4-(3H)-ones (288)were obtained in an exothermic reaction by heating methyl 2-acylamino3-thiophenecarboxylates (286)with N,N’-dimethylphosphordiamidate(287) up to 250°C’ 5 5 (Scheme 78). Ethyl 2-acylamino-3-pyridinecarboxylate (289) gave, on heating with excess amine hydrochloride and phosphorus pentoxide/N,N’-dimethylcyclohexylamine,a series of pyrido[2,3-d]pyrimidine-4(3H)-ones

IX. Photochemistry Photoisomerization of the dihydrofurans 8 (X = 0, n = 1) requires triphenylene as sensitizer ( E , = 285 kJ/mol) to form l-carbamoyl-lethoxycarbonylcyclopropanes (292)’’’ (Scheme 79). Despite the bathochromic UV maximum (cf. Section II1,B) caused by the enaminocarbonyl

SCHEME 79

15’

0.Hrornatky and D. Binder, Monatsh. Chem. 1Q4,1343 (1973). K.E. Nielsen and E. B. Pedersen, Acta Chem. Scand., Ser. B B32,303 (1978). 0.R.Andresen and E. B. Pedersen, Liebigs Ann. Chem., 1012 (1982). H. Warnhoff, Chem. Ber. 105,748(1972).

356

HEINRICH WAMHOFF

[Sec. IX

resonance, the enamino ester moiety is not the important site for the photochemical behavior. Instead, 8 reacts as a dihydrofuran’ 5 8 via homolysis of the C-5-0 bond; rearrangement gives the stable amide group, and cyclization to cyclopropanes 292 occurs. Upon UV irradiation, the heteroaromatic isoxazoles 35 rearrange similarly-most likely via azirines (293)’ 59-to afford, by photocleavage of 293, nitrilylides (294)140*’60and finally the isomeric 1,3-oxazoles 295.’” However, ethyl 5-aminoisoxazole-4-carboxylate(34)isomerizes by another pathway. Similar to some thermal reactions,161 reorganization of the nitrile function in 295 affords the vinylamine 2%lS7 (Scheme 80). Similar results are known for benzisoxazoles.16’

SCHEME 80

I6O

Cf. D. W. Boykin and R. E. Lutz, J . Am. Chem. SOC.86, 5046 (1964); D. E. McGreer, M. G. Vinje, and R. S. McDaniel, Can. J. Chem. 43, 1417 (1965); J. Wieman, N. Thoai, and F. Weisbuch, Bull. SOC.Chim. Fr., 575 (1966). E. F. Ullman, and B. Singh, J. Am. Chem.SOC.88,1844 (1966); B. Singh and E. F. Ullman, ihid. 89, 691 1 (1967); B. Singh, A. Zweig, and J. B. Gallivan, ibid. 94, 1199 (1972). A. Padwa, M. Dharan, J. Smolanofl, and S. E. Wetmore, Pure Appl. Chem. 33, 269 (1973); H.Schrnid et a/., ibid., 339; A. Padwa, J. Smolanoff, and A. Tremper, J . Org. Chem. 41, 543 (1976).

161 16*

A. Quilico, in “Heterocyclic Compounds” (R. H. Wiley, ed.), p. 44tf.Wiley, New York, 1962. H. Goth and H. Schrnid, Chimia 20,148 (1966).

Sec. X.A]

HETEROCYCLIC B-ENAMINO ESTERS

357

Upon UV irradiation, ethyl 5-amino-l-phenyl-l,2,3-triazole-4-carboxylate (40) does not expel N2 to give ketenimines or aziridines. Instead, in the presence of triphenylene as photosensitizer, 40 is smoothly isomerized, as a first example of a photo-Dimroth rearrangement,’63to ethyl 5-anilino-1,2,3triazole-4-carboxylate (298).164The mechanism is explained by a radical rearrangement, e.g., 2971-297111 (cf. Scheme 8 1). This isomerization type was observed also with 5-amino- 1,4-diphenyl-1,2,3-triazoles.’6s 40-

hv

I

I

Ph

Ph

(29711)

TI I

H

NHPh

H

SCHEME81

X. Heterocyclic /&Enamino Nitriles

A. SYNTHESES The syntheses, properties, and chemistry of heteroaromatic 8-enamino nitriles have been reviewed extensively.166 Therefore, this section deals mainly with partially saturated heterocyclic /I-enamino nitriles; in addition, some further reactions of heteroaromatic /3-enamino nitriles are briefly described. Cf. D. J. Brown, in “Mechanisms of Molecular Migrations” (B. S. Thyagarajan, ed.), Vol. 1, p, 209. Wiley (Interscience), New York 1968. 164 G.Szilagyi and H. Wamhoff, Acta Chim. Acad. Sci. Hung. 89,265 (1976)[ C A 86, 121,238t (1977)J Y. Ogata, K. Tagaki, and E. Hayashi, Bull. Chem. SOC.Jpn. 50,2505 (1977). 166 E. C. Taylor and A. McKillop, Adu. Org. Chem. 7,1(1970). 163

358

[Sec. X.A

HEINRICH WAMHOFF

2-Amino-3-cyano-4,5-dihydrofurans (299)are prepared from oxiranes and sodium m a l ~ n o d i n i t r i l e , ' ~ ~and - ' ~ ~the corresponding dihydrothiophenes (300)are similarly obtained by treatment of thiirane with sodium malonodinitrile. But the procedures reported' 7 0 had to be modified considerably; a temperature of -20°C and dimethoxyethane as solvent gave better yields'69 (Scheme 82). Attempts to transfer this synthesis to N-tosylaziridine (301),

/CN K'-:CH \ CN

+\/

7

-

NH2

1

HCN CN I

Tos

II

Tos

1-1

1

II

I

Tos

SCHEME 82

'

previously successfully applied in the generation of a pyrrolenamino ester,' lead at first to complex mixtures. But upon refluxing both components, a 2:ladduct was isolated; this proved to be pyrrolo[2,3-d]pyridine 303. The desired enamino nitrile 302 can be formulated only as an elusive intermediate. However, at 10°C in 1,2-dimethoxyethane,another 1:Zspiro adduct (304) is formed,16' similar to a reaction of aziridines and malonic esters.17' But employing - 10°C and the same conditions as above, the desired 1:l adduct can be obtained in good yield. 69 Independently, workers in Japan described an analogous synthesis of ethyl 2-amino-3-cyano-4,5-dihydropyrrole-l-

'

Hisamitsu Seiyaku Co. Ltd., Japanese Patent 72/05,255 (1972) (inventors: K. Yamazaki and T. Matsuda) [CA 76, 140492(1972)J S. Morgenlie, Acta Chem. Scand. 24, 365 (1970). 169 H. Wamhoff and H. A. Thiemig, Chem. Ber. 118 (1985), in press. Hisamitsu Pharm. Co. Ltd., Jpn Kokai Tokkyo Koho 74, 13, 164 (1974) (inventors: T. Matsuda, K. Yamazaki, H. Ide, K. Noda, and K. Yamagata) [CA 81, P13,375y (1975)l; K. Yamagata, Y. Tomioka, M. Yamazaki, T. Matsuda, and K. Noda, Chem. Pharm. Bull. 30,4396 (1982) [CA 98, 179135~(1983)J ''I M. Kojima, T. Kawakita, and K. Kudo, Yakugaku Zasshi 92, 465 (1972) [CA 77, 34,230e ( 1972)]. 16'

Sec. X.A]

359

HETEROCYCLIC /%ENAMINO ESTERS

carboxylate (302a) and its aromatization (302b)by means of chloranil' 'la (Scheme 83). The 5,6-dihydro-4H-pyranenamino nitrile 305 is obtained in low Tos

I

e?i ? / I

Tos

301

+ K+-

(304)

\ LC2 I

Tos

C0,Et

I

CO,Et

I C0,Et

SCHEME 83

yield from potassium malonodinitrile by fast addition of 3-bromopropanole.'68 This procedure could not be transferred to the sulfur analog (Scheme 84).

SCHEME 84 "la

M. Sonoda, N. Kuriyama, Y. Tomioka, and M. Yamazaki, Chem. Pharm. Bull. 30,2357 (1982) [CA 97,162,744a (1982)l.

360

[Sec. X.C

HEINRICH WAMHOFF TABLE 111

COInpanSOn Of the 6

3c-3OF SOME /&ENAMINO ESTERS AND NIT RILE^

Compound

8 71 72 299 300 302 305

X

Y

I T - 3 (ppm)

N-TOS 0

C0,Et C0,Et C02Et CN CN CN CN

73.6 90.66 92.1 47.1 65.2 57.5 53.9

n

1

0

2

S S

1 1

1 1 2

0

S

B. PROPERTIES AND COMPARISON WITH ENAMINO ESTERS In the IR spectra, the partially saturated heterocyclic /?-enaminonitriles do not exhibit the normal group frequencies that the corresponding esters display. The comparison of the "C-NMR spectra of nitriles 299,300,302,and 305 with those of the esters 8,71, and 72 reveal for the nitriles a greater highfield shift of 27 ppm (Table 111).As a consequence, it is concluded that in the enamino nitriles the double bond is more polarized than that of the corresponding esters; several canonical forms can be discussed (Scheme 85). This difference in polarization (8, 71, and 72 versus 299,300,302,and 305) leads to several significant differences in the chemical behavior, which are briefly discussed in the following sections.

-

-

2 : Q

A

-.rL /N-

. + .

QCN..*.**..NH, B

NHZ ...**...

0,

t .

C

SCHEME 85

C. HETEROCYCLIZATION REACTIONS The enamino nitriles 299, 300, and 302 react smoothly with various isocyanates to afford heterocondensed 4-amino-2-oxopyrimidines (306).'72

H. Wamhoff and H. A. Thiemig, Chem. Ber. 118 (1985), in press.

Sec. X.C]

HETEROCYCLIC b-ENAMINO ESTERS

36 1

The 2: 1 adduct 303 gives rise to the pyrrolo[3’,2’:5,6]pyrido[2,3-d]pyrimidine 307. Similar results have been reported for imidazolenamino nitriles’ 73 (Scheme 86). While enamino esters, on heating with formamide, afford, in a

diO &Io NHZ NH

I

H

Tos

SCHEME 86

clean reaction, heterocondensed pyrimidines (cf. Section V,B), the corresponding enamino nitriles 299 give under the same conditions di- and trimerization products 3081, 30811,’74 and 309, respectively. (Scheme 87). The structure of 309 was established by X-ray analysis.’ 74 Pyrazol- and 1,2,3-triazolenamino nitriles (310) are known to afford base-catalyzed dimerization products such

NH2

R I

SCHEME 87

‘73 A.

F. Cook, B. A. Balder et al., J. Med. Chem. 24,947 (1981).

H.Wamhoff, H. A. Thiemig, E. Friedrichs, and H.Puff,Chem. Ber. (in press).

362

[Sec. X.C

HEINRICH WAMHOFF

as 311,which are related to 3081/30811.'75 With ethyl cyanoacetate, 299 gives, via the condensation intermediate 312, a novel tricyclic system (313)'69 (Scheme 88). Heteroaromatic p-enamino nitriles under these conditions annelate a pyridine ring to give 314 and 315.'76 In contrast to the broad applicability of heterocyclic p-enamino esters, the corresponding enamino nitriles with imido esters, phenylazide, or diamines, thermally as well as photochemically, give no reasonable products.

R X=CH,N

/COzEt 299 + CH \2CN

+299

C0,Et

D

NC'\

LNH

SCHEME 88

'" D. R. Sutherland and G. Tennant, J . Chem. SOC.C, 706 (1971); A. Kreutzberger and K. Burgwitz, Chem.-Ztg. 104,175 (1980). W. Zimmermann, K. Eger, and H. J. Roth, Arch. Pharm. (Weinheim Ger.) 309, 597 (1976); K. Gewald, H. Schafer, and K. Sattler, Monatsh. Chem. 110, 1189 (1979).

Sec. X.D]

363

HETEROCYCLIC/%ENAMINOESTERS

D. DIMROTH REARRANGEMENTS TO THIENOAND FURO[2,3-d]PYRIMIDOPHANES

Similar to the heteroannelation reactions with lactim ethers described in Section V,B,the enamino nitriles 299, 300, and 305 on heating with lactim ethers having up to a nine-membered ring afford the linear annelated tricycles 317.172 However, employing medium-ring-sized lactim ethers (m2 7 and 11) the imino tricycles 317 react in a Dimroth-type r e a ~ t i o n ' ~ ~ to. 'afford ~~ heterocondensed pyrimidophanes (318) as the thermodynamic products (Scheme 89). Such Dimroth rearrangements are influenced by water and other NH

X = O , S ; n = 1,2

(316)

(317)

m = 3-1

HN-

m=7,11

SCHEME 89

nucleophiles such as alcohols and amines."* Thus in the presence of butanol, the rearrangement can be formulated to proceed via a macrocyclic intermediate (317a) to give the phanes 318 (cf. Scheme 90). Dimroth rearrangements of this type have been recently observed on open-chain, carbocyclic,

177

17*

H. C. Carrington, F. H. Curd, and D. N. Richardson, J. Chem. SOC.,1858 (1955); D.J. Brown, E. Hoerger, and S. F. Mason, ibid., 4035. D. J. Brown, P. W. Ford, and M. N. Paddon-Row,J . Chem. SOC.C, 1452 (1968).

364

HEINRICH WAMHOFF

[Sec. X.D

NH

OBu (3170)

SCHEME90

and heteroaromatic enamino nitriles with lactim ethers of ring sizes rn = 6,7, 9, and 11. These rearrangements (319 + 320) occur spontaneously or in the presence of base^"^*'^^ (Scheme 91). NH d

,

z

C

H

2 )m

SCHEME9 1

2-Benzamido-3-cyano-4,5-dihydrothiophenes (321) cyclize at 120°C with cyclohexylamine, morpholine, piperidine, and pyrrolidine to the corresponding 4-amino-2-phenyl-5,6-dihydrothieno[2,3-d]pyrimidines(322).18' However, when 321 and 2 equivalents of dimethylamine hydrochloride in pyridine were refluxed for 5 hr, the 4-oxothieno[2,3-d]pyrimidine 323 was formed nearly quantitatively'" (Scheme 92). Ethyl N-(3-cyano-4,5-dihydro2-thieny1)oxamates (324) give, with cyanomethylene compounds in the presence of triethylamine, thieno[2,3-d]pyrimidines (325).

D. J. Brown and K. lenaga, J.C.S. Perkin I2182 (1975); Aust. J . Chem. 28, 119 (1975). K. lenaga and W. Pfleiderer, Liebigs Ann. Chem., 1872 (1979). la' K. Yamagata, Y. Tomioka, M. Yamazaki, and K. Noda, Chem. Pharm. Bull. 31,401 (1983)[CA 99,88,145d (1983)l. S. Hachiyama, K. Koyanagi, Y. Tomioka, and M. Yamazaki, Chem. Pharm. Bull. 31, 1177 (1983) [CA 99, 158,361~(1983)l.

Sec. X.E]

HETEROCYCLIC 1-EN AMINO ESTERS

Ph\

365 /R

N

NHCOPh

/ \

NHCOCOzEt + ICH,COR CN

-R ~ i c H R

SCHEME92

E. MISCELLANEOUS REACTIONS OF HETEROAROMATIC /?-ENAMINO NITRILES 2-Amino-3-cyanopyrroles (326)are versatile starting materials for the easy synthesis of 4-amino-7H-pyrrolo[2,3-d]pyrimidines(327)by treatment with triethyl orthoformate and ammonia.183.'84 The 1,2-diamino-3-cyanopyrrole 328 affords with diacetyl in acetic acid a pyrrolo[ 1,2-b]-as-triazine (329)Ia4 (Scheme 93). Malonodinitrile, sulfur, and bases afford the diaminodicyanothiophenes 330 and 331.'66 Compound 331 yields, with 2 equivalents of formamide, 4,9-diaminothieno[2,3-d:4,5-d']dipyrimidines(332)'" (Scheme 94). Furthermore, 2-amino-3-cyanothiophenes(333)react with ethyl aminocrotonate. Cyclization of the intermediate 334 with sodium ethoxide gives l a 3 E.

C. Taylor and R. W. Hendess, J . Am. Chem. SOC.86,951 (1964); 87,1995 (1965). K. Gewald and M. Hentschel,J . Prakt. Chem. 318,663 (1976); with ethoxyvinylderivatives:cf. T. Kurihara, K. Nasu, and Y. Adachi, J . Heterocycl. Chem. 20,81(1983). l a 5 K. Gewald, M. Kleinert, B. Thiele, and M. Hentschel, J . Prakt. Chem. 314,303 (1972).

3 66

QZ2 H

[Sec. X.E

HEINRICH WAMHOFF

H

H

OR

I NH 2

SCHEME94

SCHEME 95

H

Sec. XI]

HETEROCYCLIC /%ENAMINO ESTERS

367

4-aminothieno[2,3-b] pyridines (335).la6 4-Aminothieno [2,3-d] pyrimidines (337)are also formed by heating 2-acylaminothiophene-3-carbonitriles(336) with primary alkyl amines, P,05, and cyclohexyldimethylamine’87 (Scheme 95).

XI. Conclusion and Outlook This review on heterocyclic fl-enaminoesters and related compounds is not exhaustive. Instead, it aims to depict synthetic trends and preparative applicabilitiesof this rather versatile class of compounds. It is hoped that this review might stimulate a broad application of these compounds to the synthesis of novel heterocycles and especially natural products,’ 8 8 biologically active substance^,'^^ and drugs.’90 One example is the investigation of the isosteric properties of benzene and thiophene moieties. Some thiophene analogues of 4-quinazolones, namely, thieno[2,3-d]pyrimidines, showed significant antimicrobial activity”’ as well as antiinflammatory and anticonvulsant properties (Scheme 96). Thieno analogues of the alkaloids echinorine (338)and echinopsine (339) have been obtained from thiopheneenamino ester derivatives, leading to thieno [3,2b] pyridines. 9 2

’

Me

I 1-

Me I

SCHEME96

I. Lalezari, J . Heterocycl. Chem. 16,603 (1979). K. E. Nielsen and E. B. Pedersen, Chem. Scr. 18,245 (1981) [CA 96,122739a (1982)l. l s 8 Cf. V. Snieckus, Sur. Prog. Chem. 9,122 (1980). 189 Cf. A. Albert, Intra-Sci. Chem. Rep. 8,55 (1974). 190 Cf. D. Lednicer and L. A. Mitscher, “The Organic Chemistry of Drug Synthesis.” Wiley (Interscience), New York 1977. 191 M. B. Devani, C. J. Shishoo, U. S . Pathak, S. H. Parikh, G. F. Shah, and A. C. Padhya, J . Pharm. Sci. 65,660 (1976). 19* J. M. Barker, P. R. Huddleston, and A. W. Jones, J . Chem. Res. Synop., 393 (1978);J . Chem. Res., Miniprint, 4701 (1978). ls6 Is’

368

HEINRICH WAMHOFF

[Sec. XI

ACKNOWLEDGMENTS This review would not have been possible without the skillful and untiring activity of my co-workers and collaborators: Miss Dr. A. Atta, Dr. H. Durbeck, Prof. H. M. Elnagdi, Dr. M. Ertas, Dr. L. Farkas, E. Gierke, Dr. G. HalTmanns, Dr. J. Hartlapp, Dr. G. Hendrikx, Prof. Zhi-tang Huang, J. Keuler, Dr. G. Kunz, Prof. J. Lehmann, Dr. L. Lichtenthaler, Dr. C. Materne, J. Nagelschmitz, Dr. H. Schmidt, Prof. P. Sohar, Dr. G. Szillgyi, Dr. H. A. Thiemig, Dr. K. Wald, Dr. C. von Waldow, Dr. B. Wehling, Dr. Shi-yan Yang, and M.Zahran. I thank the Deutsche Forschungsgemeinschaft, the Minister fur Wissenschaft und Forschung des Landes Nordrhein-Westfalen,and the Fonds der Chemischen Industrie for support and Bayer AG and Hoechst Aktiengesellschaftfor chemicals.

Cumulative Index of Titles A

B

Acetylenecarboxylic acids and esters, reactions with N-heterocycfic compounds. I, 125, Acetylenecarboxylic esters, reactions with nitrogen-containing heterocycles, 23, 263 Acefylenic esters. synthesis of heterocycles through nucleophilic additions to, 19, 297 Acid-catalyzed polymeriza~ionof pyrroles and indoles. 2, 287 f-Amino effect, 14, 211 Aminochromes, 5, 205 Anils, olefin synthesis with, 23, 171 Annelation of a pyrimidine ring to an existing ring, 32, I Annulenes, N-bridged. cyclazines and, 22, 32 I Anfhracen- I .4-imines, 16, 87 Anthranils, 8, 277; 29, I Applications of NMR spectroscopy to indole and its derivatives, 15, 277 Applicationsof the Hammett equation to heterocyclic compounds. 3, 209; 20, I Arene oxides, chemistry of, 37,67 Aromatic azapentalenes. 22, 183 Aromatic quinolizines, 5, 291; 31, I Aromaticity of heterocycles. 17, 255 Aza analogs of pyrimidine and purine bases, 1, 189 7-Arabicyclo[2.2. I Ihepta-2.5-dienes. 16, 87 I -AzabicycloI3. I .Ojhexanes and analogs with further heteroatom substitution. 27, I Azapenfalenes, aromatic, chemistry of, 22, 183 Azines. reactivity with nucleophiles, 4, 145 Azines, theoretical studies of. physicochemical properties of reactivity of. 5, 69 Azinoazines. reactivity with nucleophiles. 4, I45 I-Azirines, synthesis and reactions of. 13, 45 Azodicarbonyl compounds in hetrocyclic synthesis, 30, I

Barbituric acid, recent progress in chemistry of, 38, 229 Base-catalyzed hydrogen exchange, 16, 1 1-, 2-, and 3-Benzazepines, 17, 45 Benzisothiazoles, 14, 43; 38, 105 Benzisoxazoles. 8, 277 Benzoazines. reactivity with nucleophiles. 4,

369

I45

Benzo[c]cinnolines. 24, 151 I 3-Benzodiazepines. 17, 27 Benzolblfuran and derivatives. recent advances in chemistry of, Part I. occurrence and synthesis, 18, 337 Benzolclfurans, 26, 135 Benzofuroxans. 10, I; 29, 251 W-Benzopyrans (chrom-3-enes), 18, I59 Benzothiazines 1,2- and 2, I-benzothiazines and related compounds, 28, 73 1,4-benzothiazines and related compounds, 38, 135 Benzolblthiophene chemistry, recent advances in. 11, 177; 29, 171 Benzolclthiophenes, 14, 33 I 1.2.3-(Benzo)triazines.19, 215 Benzyne, reactions with heterocyclic compounds, 28, 183 Biological pyrimidines. tautomerism and electronic structure of, 18, 199 Bipyridines, 35, 281

C 9H-Carbazoles. recent advances in. 35, 83 Carbenes and nitrenes, intramolecular reactions, 28, 23 I reactions with heterocyclic compounds. 3, 57 Carbolines, 3, 79 Cationic polar cycloaddition. 16, 289 (19, xi)

3 70

CUMULATIVE INDEX OF TITLES

Chemistry of arene oxides, 37, 67 of aromatic azapentalenes, 22, 183 of barbituric acid, recent progress in, 38, 229 of benzo[b]furan, Part I, occurrence and synthesis, 18, 337 of benzolblthiophenes. 11, 177; 29, 171 of chrom-3-enes. 18, 159 of diazepines, 8, 21 of dibenzothiophenes, 16, 181 of dihydroazines, 38, I of 1,2-dioxetanes, 21, 437 of furans, 7, 377 of hydantoins, 38, 177 of isatin. 18, I of isoxazolidines, 21, 207 of lactim ethers. 12, I85 of mononuclear isothiazoles. 14, I of 4-oxy- and 4-keto- I .2,3.4-tetrahydroisoquinolines, IS, 99 of phenanthridines. 13, 315 of phenothiazines, 9, 321 of polycyclic isothiazoles, 38, 1 of I-pyridines, 15, 197 of pyrrolizines, 37, 1 of tetrazoles. 21, 323 of I .3.4-thiadiazoles. 9, 165 of thienothiophenes. 19, 123 of thiophenes. I, I Chrom-3-ene chemistry, advances in, 18, 159 Claisen rearrangements. in nitrogen heterocyclic systems. 8, 143 Complex metal hydrides. reduction of nitrogen heterocycles with. 6, 45 Covalent hydration in heteroaromatic compounds. 4, I , 43 in nitrogen heterocycles. 20, I17 Current views on some physicochemical aspects of purines. 24, 215 Cyclazines. and related N-bridged annulenes. 22, 321 Cyclic enamines and imines. 6,.147 Cyclic hydroxamic acids, 10, 199 Cyclic peroxides, 8. 165 Cyclizations under Vilsmeier conditions. 31, 207 Cycloaddition. cationic polar, 16, 289 (19, xi) (2 + 2)-Cycloaddition and ( 2 + 2)-cycloreversion reactions of heterocyclic comwunds. 21. 253

D Developments in the chemistry of furans (1952-1963), 7, 377 of Reissen compounds (1968-1978). 24, I87 Dewar heterocycles and related compounds, 31, I69 2.4-Dialkoxypyrimidines,Hilbert-Johnson reaction of. 8, I I5 Diazepines. chemistry of. 8, 21 I .4-Diazepines. 2.3-dihydro-. 17, I Diazirines. diaziridines, 2, 83; 24. 63 Diazo compounds. heterocyclic. 8, I Diazomethane. reactions with heterocyclic compounds. 2, 245 Dibenzothiophenes, chemistry of, 16, 181 Dihydroazines, recent advances in chemistry of, 38, 1 Dihydro-l,4-benzothiazines,and related compounds, 38, 135 2.3-Dihydro-1.4-diazepines, 17, I I .2-Dihydroisoquinolines.14, 279 I .2-Dioxetanes. chemistry of. 21, 437 Diquinolylmethane and its analogs, 7, 153 ~e,n-Dithienylalkanesand their derivatives. 32, 83 1.2- and 1.3-Dithiolium ions, 7, 39; 27, 151 I .3-Dithiol-3-thiones and I .2-dithiol-3-ones. 31.63

E Electrochemical synthesis of pyridines, 37, 167 Electrolysis of N-heterocyclic compounds part I. 12, 213 part II, 36, 235 Electronic aspects of purine tautomerism. 13, 77 Electronic structure of biological pyrimidines. tautomerism and. 18, 199 Electronic structure of heterocyclic sulfur compounds, 5, I Electrophilic substitutions of five-membered rings, 13, 235 P-Enamino esters, heterocyclic, as heterocyclic synthons, 38, 299 .rr-Excessive heteroannulenes, medium-large and large, 23, 55

F Ferrocenes. heterocyclic, 13, I Five-memberedrings. electrophilic substitutions of. 13, 235

CUMULATIVE INDEX OF TITLES Formation of anionic o-adducts from heteroaromatic compounds. 34, 305 Free radical substitutions of heteroaromatic compounds. 2, 131 Furans development of the chemistry of (19521963). 7, 377 dibenzo-, 35, I recent advances in chemistry. Part I. 30, 167 Furoxans, 29. 251

37 1

Heterocyclic chemistry, literature of, 7, 225; 25, 303 Heterocyclic compounds application of Hammett equation to, 3, 209; 20, I (2 t 2)-cycloaddition and (2 + 2)-cycloreversion reactions of, 21, 253 halogenation of, 7, I isotopic hydrogen labeling of, 15, 137 mass spectrometry of, 7, 301 quatemization of, 3, I: 22, 71 reactions of, with carbenes, 3, 57 G reactions of diazomethane with, 2, 245 N-Heterocyclic compounds Grignard reagents. indole. 10,43 electrolysis of, 12, 213 reaction of acetylenecarboxylic acids and esters with, 1, 125; 23, 263 H Heterocyclic diazo compounds, 8, I Halogenation of heterocyclic compounds. 7, 1 Heterocyclic ferrocenes, 13, I Hammett equation. applications to heterocyclic Heterocyclic oligomers. IS, I compounds. 3, 209; 24, I Heterocyclic pseudobases, 1, 167; 25, I Hetarynes, 4, 121 Heterocyclic sulphur compounds, electronic Heteroadamantane, 30, 79 structure of, 5, 1 Heteroannulenes, medium-large and large n- Heterocyclic synthesis excessive, 23, 55 heterocyclic p-enamino esters and, 38, 299 Heteroaromatic compounds from nitrilium salts under acidic conditions, N-aminoazonium salts. 29, 71 6, 95 free-radical substitutions of, 2, 131 through nucleophilic additions to acetylenic homolytic substitution of, 16, 123 esters, 19, 279 nitrogen. covalent hydration in, 4, I , 43 thioureas in, 18, 99 prototropic tautomerism of, 1, 3 I I, 339; 2, I. Hilbert-Johnson reaction of 2,4-dialkox27; Suppl. I ypyrimidines, 8, I15 quaternization of, 22, 7 I Homolytic substitution of heteroaromatic comHeteroaromatic N-imines, 17, 213; 29, 71 pounds, 16, 123 Heteroaromatic nitro compounds, ring synthesis Hydantoins, chemistry of, 38, 177 of. 25, 113 Hydrogen exchange Heteroaromatic radicals, Part 1. general propbase-catalyzed, 16, I erties; radicals with Group V ring heterone-step (labeling) methods, 15, 137 oatoms, 25, 205; Part II. radicals with Hydroxamic acids, cyclic, 10, 199 Group VI and Groups V and VI ring heteroatoms, 27, 31 I Heteroaromatic substitution, nucleophilic, 3, 285 lmidazole chemistry Heterocycles advances in, 12, 103; 27, 241 aromaticity of, 17, 255 2H-. 35, 315 nomenclature of, 20, 175 4H-, 35,413 photochemistry of, 11, I lndole Grignard reagents, 10, 43 by ring closure of ortho-substituted rIndole(s) anilines, 14, 211 acid-catalyzed polymerization, 2, 287 Heterocyclic betaine derivatives of altemant and derivatives, application of NMR hydrocarbons, 26, 1 spectroscopy to, 15, 277

372

CUMULATIVE INDEX

lndolizine chemistry, advances in, 23, 103 Indolones, isatogens and, 22, 123 Indoxazenes. 8, 277; 29, I Isatin, chemistry of, 18, I lsatogens and indolones. 22, 123 lsatoic anhydrides, uses in heterocyclic synthesis, 28, 127 Isoindoles, 10, 113; 29, 341 Isoquinolines I,2-dihydro-. 14, 279 4-oxy- and 4-keto- I,2,3,4-tetrahydro-, 15,99 Isothiazoles. 14, 107 recent advances in the chemistry of monocyclic, 14, 1 polycyclic, recent advances in chemistry of, 38, 105 Isotopic hydrogen labeling o f heterocyclic compounds, one-step methods. IS, 137 lsoxazole chemistry, recent developments in. 2, 365; since 1963, 25, 147 Isoxazolidines. chemistry of. 21, 207

L Lactim ethers. chemistry of. 12, 185 Literature of heterocyclic chemistry, 7, 225; 25, 303

M Mass spectrometry of heterocyclic compounds, 7, 301 Medium-large and large n-excessive heteroannulenes. 23, 55 Meso-ionic compounds, 19, I Metal catalysts. action on pyridines, 2, 179 Monoazaindoles, 9, 27 Monocyclic pyrroles. oxidation. of. IS, 67 Monocyclic sulfur-containing pyrones, 8, 219 Mononuclear heterocyclic rearrangements. 29, 141 Mononuclear isothiazoles. recent advances in chemistry of, 14, I

N Naphthalen- I.4,imines. 16, 87 Naphthyridines, 11, 124 reactivity of. toward nitrogen nucleophiles, 33,95

OF TITLES

recent developments in chemistry of, 33, 147 Nitrites and nitrilium salts. heterocyclic synthesis involving, 6, 95 Nitrogen-bridged six-membered ring systems, 16, 87 Nitrogen heterocycles Conformational equilibria in saturated sixmembered rings, 36, 1 covalent hydration in. 20, I17 reactions of acetylenecarboxylic esters with. 23, 263 reduction of, with complex metal hydrides. 6, 45 Nitrogen heterocyclic systems. Claisen rearrangements in. 8, 143 Nomenclature of heterocycles, 20, 175 Nuclear magnetic resonance spectroscopy. application to indoles. IS, 277 Nucleophiles. reactivity of azine derivatives with. 4. 145 Nucleophilic additions to acetylenic esters, synthesis of heterocycles through. 19, 299 Nucleophilic heteroaromatic substitution, 3, 285

0 Olefin synthesis with anils. 23, 171 Oligomers. heterocyclic, IS, I I.2.4-Oxadiazoles. 20, 65 I.3.4-Oxadiazole chemistry. recent advances in, 7, 183 I.3-Oxazine derivatives. 2, 3 II; 23, I Oxaziridines, 2, 83; 24, 63 Oxazole chemistry, advances in, 17, 99 Oxazolone chemistry new developments in. 21, 175 recent advances in, 4, 75 Oxidation of monocyclic pyrroles. IS, 67 3-0xo-2,3-dihydrobenz[d]isothiazole1,1-dioxide (saccharin) and derivatives, IS, 233 4-Oxy- and 4-keto- I,2.3,4-tetrahydroisoquinolines, chemistry of, 15, 99

P Pentazoles. 3, 373 Peroxides, cyclic, 8, 165 (see also 1.2-Dioxetanes) Phase transfer catalysis. applications in heterocyclic chemistry. 36, 175

373

CUMULATIVE INDEX OF TITLES Phenanthridine chemistry. recent developments in. 13, 315 Phenanthrolines. 22, I Phenothiazines. chemistry of. 9, 32 I Phenoxazines. 8, 83 Photochemistry of heterocycles. 11, I of nitrogen-containing heterocycles. 30, 239 of oxygen- and sulfur-containing heterocycles, 33, I Physicochemical aspects of purines, 6, I ; 24, 215 Physicochemical properties of azines. 5, 69 of pyrroles, 11, 383 3-Piperideines. 12, 43 Polyfluoroheteroaromatic compounds. 28, I Polymerization of pyrroles and indoles. acidcatalyzed. 2, I Prototropic tautomerism of heteroaromatic compounds. 1, 311. 339; 2, I . 27; Suppl. I Pseudoazulenes. 33, I85 Pseudobases. heterocyclic. 1, 167; 25, I Purine bases, aza analogs of. 1, 189 Purines physicochemical aspects of. 6, I ; 24, 2 I5 tautomerism. electronic aspects of, 13, 77 Pyrans. thiopyrans. and selenopyrans, 34, 145 Pyrazine chemistry. recent advances in, 14, 99 Pyrazole chemistry 3H-. 34, I 4H-, 34, 53 progress in. 6, 347 Pyrazolopyridines. 36, 343 Pyridazines. 9, 21 I ; 24, 363 Pyridine(s) action of metal catalysts on, 2, 179 effect of substituents on substitution in, 6, 229 synthesis by electrochemical methods, 37, 167 I .2.3.6-tetrahydro-, 12, 43 Pyridoindoles (the carboline. 3, 79 Pyridopyrimidines. 10, 149 Pyridol I .2-o]pyrimidines.chemistry of, 33,241 Pyrimidine bases, aza analogs of, 1, 189 Pyrimidines 2.4-dialkoxy-. Hilben-Johnson reaction of. 8, 115 tautomerism and electronic S ~ N C I Uof~ ~biological. 18, 199 I-Pyrindines, chemistry of, 15, 197

Pyrones. monocyclic sulfur-containing, 8, 219 Pyrroles acid-catalyzed polymerization of, 2, 287 2H- and 3H-. 32, 233 oxidation of monocyclic. 15, 67 physicochemical properties of, 11, 383 Pyrrolizidine chemistry, 5, 3 15; 24, 247 Pyrrolizines, chemistry of, 37, 1 Pyrrolodiazines. with a bridgehead nitrogen, 21, I Pyrrolopyridines, 9, 27 Pyrylium salts, syntheses. 10, 241

Q Quatem izat ion of heteroaromatic compounds, 22, 7 1 of heterocyclic compounds, 3, 1 Quinazolines. 1, 253; 24, I Quinolizines. aromatic, 5, 291 Quinoxaline chemistry developmenis 1963-1975, 22, 367 recent advances in, 2, 203 Quinuclidine chemistry, 11, 473

R Recent advances in furan chemistry. Pan I. 30, 168; Pan I I , 31, 237 Reduction of nitrogen heterocycles with complex metal hydrides. 6, 45 Reissen compounds, 9, Ij 24, 187 Ring closure of onho-substituted r-anilines, for heterocycles, 14, 21 I Ring synthesis of heteroaromatic nitro compounds. 25, I13

S Saccharin and derivatives. 15, 233 Selenazole chemistry. present state of, 2, 343 Selenium-nitrogen heterocycles, 24, I09 Selenophene chemistry, advances in, 12, I Selenophenes. 30, I27 Six-membered ring systems, nitrogen bridged, 16, 87

374

CUMULATIVE INDEX OF TITLES

Substitution(s) electrophilic. of five-membered rings, 13, 235 homolytic. of heteroaromatic compounds, 16, I23 nucleophilic heteroaromatic. 3, 285 in pyridines, effect of substituents, 6, 229 Sulfur compounds electronic structure of heterocyclic, 5, I four-membered rings, 35, 199 Sulfur transfer reagents in heterocyclic synthesis, 30, 47 Synthesis, of tetracyclic and pentacyclic condensed thiophene systems, 32, 127 Synthesis and reactions of I-azirines. 13, 45 Synthesis of heterocycles heterocyclic p-enamino esters as synthons in, 38, 299 from nitrilium salts under acidic conditions, 6, 95 through nucleophilic additions to acetylenic esters, 19, 279 thioureas in, 18, 99

T Tautomerism electronic aspects of purine, 13, 77 and electronic structure of biological pyrimidines. 18, 199 prototropic, of hetemaromatic compounds, 1, 3 I I. 339: 2, I . 27; Suppl. I Tellurophene and related compounds, 21, I19 I .2,3.4-Tetrahydroisoquinolines.4-oxy- and 4keto-. 15, 99 I ,2.3.6-Tetrahydropyridines,12, 43

Tetrazole chemistry. recent advances in, 21, 323 Theoretical studies of physicochemical properties and reactivity of azines. 5, 69 I ,2,4-Thiadiazoles, 5, 119; 32, 285 I .2,5-Thiadiazoles, chemistry of. 9, 107 I .3,4-Thiadiazoles, recent advances in the chemistry of, 9, 165 Thiathiophthenes ( I ,6,6aS1"-trithiapentalenes), 13, 161 I ,2.3,4-Thiatriazoles, 3, 263; 20, 145 1,4-Thiazinesand their dihydro derivatives, 24, 293 4-Thiazolidinones. 2!5, 83 Thienopyridines. 21, 65 Thienothiophenes and related systems, chemistry of. 19, 123 Thiochmmanones and related compounds. 18, 59 Thiocoumarins, 26, I I5 Thiophenes. chemistry of, recent advances in, 1, I Thiopyrones (monocyclic sulfur-containing pyrones). 8, 219 Thioureas in synthesis of heterocycles, 18, 99 Three-memberedrings with two heteroatoms. 2, 83; 24, 63 Transition organometallic compounds in heterocyclic synthesis. use of, 30, 321 1.3.5-, 1.3.6-, 1.3,7-, and 1.3.8-Triazanaphthalenes, 10, 149 1.2.3-Triazines. 19, 215 I .2,3-Triazoles, 16, 33 A2-1,2,3-Triazolines,37,217 A3- and A4-1,2,3-Triazolines,37,351 Triazolopyridines, 34,79 I .6,5aS'V-Trithiapentalenes,13, 161